156:
next amino acid to be added. This cycle is repeated until the desired sequence has been synthesized. SPPS cycles may also include capping steps which block the ends of unreacted amino acids from reacting. At the end of the synthesis, the crude peptide is cleaved from the solid support while simultaneously removing all protecting groups using a reagent such as trifluoroacetic acid. The crude peptide can be precipitated from a non-polar solvent like diethyl ether in order to remove organic soluble byproducts. The crude peptide can be purified using
430:, sold commercially under various names such as "T3P", has become a useful reagent for amide bond formation in commercial applications. It converts the oxygen of the carboxylic acid into a leaving group, whose peptide-coupling byproducts are water-soluble and can be easily washed away. In a performance comparison between propanephosphonic acid anhydride and other peptide coupling reagents for the preparation of a nonapeptide drug, it was found that this reagent was superior to other reagents with regards to yield and low epimerization.
63:
439:
281:
834:
with thiol protecting groups. Different thiol protecting groups provide multiple dimensions of orthogonal protection. These orthogonally protected cysteines are incorporated during the solid-phase synthesis of the peptide. Successive removal of these groups, to allow for selective exposure of free thiol groups, leads to disulfide formation in a stepwise manner. The order of removal of the groups must be considered so that only one group is removed at a time.
758:
566:
893:, the yield drops if only it is used in the creation of long or highly polar peptides. Fragment condensation is better than stepwise elongation for synthesizing sophisticated long peptides, but its use must be restricted in order to protect against racemization. Fragment condensation is also undesirable since the coupled fragment must be in gross excess, which may be a limitation depending on the length of the fragment.
4138:
217:
4162:
465:
712:(TIPS) are most commonly added during the final cleavage in order to prevent side reactions with reactive cationic species released as a result of side chain deprotection. Nevertheless, many other scavenger compounds could be used as well. The resulting crude peptide is obtained as a TFA salt, which is potentially more difficult to solubilize than the fluoride salts generated in Boc SPPS.
631:
4150:
289:
976:
sulfur atom from a second cysteine in a different part of the protein. These bridges help to stabilize proteins, especially those secreted from cells. Some researchers use modified cysteines using S-acetomidomethyl (Acm) to block the formation of the disulfide bond but preserve the cysteine and the protein's original primary structure.
2179:
838:
conditions of solid-phase synthesis. Third, the removal of the thiol protecting group must be such that it leaves intact other thiol protecting groups, if orthogonal protection is desired. That is, the removal of PG A should not affect PG B. Some of the thiol protecting groups commonly used include the acetamidomethyl (Acm),
273:
975:
The strategy for the solid-phase synthesis of cyclic peptides is not limited to attachment through Asp, Glu or Lys side chains. Cysteine has a very reactive sulfhydryl group on its side chain. A disulfide bridge is created when a sulfur atom from one
Cysteine forms a single covalent bond with another
450:
Three primary types of solid supports are: gel-type supports, surface-type supports, and composites. Improvements to solid supports used for peptide synthesis enhance their ability to withstand the repeated use of TFA during the deprotection step of SPPS. Two primary resins are used, based on whether
984:
Off-resin cyclization is a solid-phase synthesis of key intermediates, followed by the key cyclization in solution phase, the final deprotection of any masked side chains is also carried out in solution phase. This has the disadvantages that the efficiencies of solid-phase synthesis are lost in the
155:
The general SPPS procedure is one of repeated cycles of alternate N-terminal deprotection and coupling reactions. The resin can be washed between each steps. First an amino acid is coupled to the resin. Subsequently, the amine is deprotected, and then coupled with the activated carboxyl group of the
446:
Solid supports for peptide synthesis are selected for physical stability, to permit the rapid filtration of liquids. Suitable supports are inert to reagents and solvents used during SPPS and allow for the attachment of the first amino acid. Swelling is of great importance because peptide synthesis
872:
The first article relating to continuous flow peptide synthesis was published in 1986, but due to technical limitations, it was not until the early 2010's when more academic groups started using continuous flow for the rapid synthesis of peptides. The advantages of continuous flow over traditional
837:
Thiol protecting groups used in peptide synthesis requiring later regioselective disulfide bond formation must possess multiple characteristics. First, they must be reversible with conditions that do not affect the unprotected side chains. Second, the protecting group must be able to withstand the
3362:
Kapusta DR, Thorkildsen C, Kenigs VA, Meier E, Vinge MM, Quist C, Petersen JS (August 2005). "Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity".
833:
The formation of multiple native disulfides remains challenging of native peptide synthesis by solid-phase methods. Random chain combination typically results in several products with nonnative disulfide bonds. Stepwise formation of disulfide bonds is typically the preferred method, and performed
792:
The use of the
Bergmann-Zervas method remained the standard practice in peptide chemistry for two full decades after its publication, superseded by newer methods (such as the Boc protecting group) in the early 1950s. Nowadays, while it has been used periodically for Ξ±-amine protection, it is much
192:
bond-formation conditions are required. To illustrate the impact of suboptimal coupling yields for a given synthesis, consider the case where each coupling step were to have at least 99% yield: this would result in a 77% overall crude yield for a 26-amino acid peptide (assuming 100% yield in each
136:
The solid support consists of small, polymeric resin beads functionalized with reactive groups (such as amine or hydroxyl groups) that link to the nascent peptide chain. Since the peptide remains covalently attached to the support throughout the synthesis, excess reagents and side products can be
53:
Chemical synthesis enables the incorporation of non-genetically coded amino acids, mirror-image D-amino acids, modification of the peptide backbone, and the introduction in controlled fashion of other modifications to the covalent structure of a peptide in order to control its folded secondary
414:(HOAt). Although these reagents can lead to the same activated ester intermediates as a carbodiimide reagent, the rate of activation is higher due to the high electrophilicty of these cationic reagents. Amidinium reagents are capable of reacting with the peptide N-terminus to form an inactive
49:
The chemical synthesis of peptides can be carried out using classical organic chemistry techniques in organic solvents, although these have been replaced in most research and development settings by solid phase peptide synthesis (see below). Chemical peptide synthesis in solution retains its
971:
on a solid support. A variety of cyclization reagents can be used such as HBTU/HOBt/DIEA, PyBop/DIEA, PyClock/DIEA. Head-to-tail peptides can be made on the solid support. The deprotection of the C-terminus at some suitable point allows on-resin cyclization by amide bond formation with the
784:
in 1932. Hence, this became known as the
Bergmann-Zervas synthesis, which was characterised "epoch-making" and helped establish synthetic peptide chemistry as a distinct field. It constituted the first useful lab method for controlled peptide synthesis, enabling the synthesis of previously
160:. The purification process, especially of longer peptides can be challenging, because cumulative amounts of numerous minor byproducts, which have properties similar to the desired peptide product, have to be removed. For this reason so-called continuous chromatography processes such as
581:(TFA). This forms a positively charged amino group in the presence of excess TFA (note that the amino group is not protonated in the image on the right), which is neutralized and coupled to the incoming activated amino acid. Neutralization can either occur prior to coupling or
849:
Using this method, Kiso and coworkers reported the first total synthesis of insulin in 1993. In this work, the A-chain of insulin was prepared with following protecting groups in place on its cysteines: CysA6(But), CysA7(Acm), and CysA11(But), leaving CysA20 unprotected.
45:
are used to block the alpha-amino group of the carboxyl-actvated amino acid in order to prevent uncontrolled polymerzation; other protecting groups are used to prevent side reactions with reactive functional groups present in the side chains of certain amino acids.
696:. The exposed amine is therefore neutral, and consequently no neutralization of the peptide-resin is required, as in the case of the Boc/Bzl approach. The lack of electrostatic repulsion between the peptide chains can lead to increased risk of aggregation with Fmoc/
171:
due to the exponential accumulation of by-products, and typically peptides and proteins in the range of 70 amino acids are pushing the limits of synthetic accessibility. Synthetic difficulty also is sequence dependent; typically aggregation-prone sequences such as
1650:
Carpino, Louis A.; Imazumi, Hideko; El-Faham, Ayman; Ferrer, Fernando J.; Zhang, Chongwu; Lee, Yunsub; Foxman, Bruce M.; Henklein, Peter; Hanay, Christiane; MΓΌgge, Clemens; Wenschuh, Holger; Klose, Jana; Beyermann, Michael; Bienert, Michael (1 February 2002).
873:
batch methods is the ability to heat reagents with good temperature control, allowing the speed of reaction kinetics while minimising side reactions. cycles times vary from 30 seconds, up to 6 minutes, depending on reaction conditions and excess of reagent.
354:). Nucleophilic attack of the carboxylic acid on the electrophilic amidinium or phosphonium moiety leads to a short lived intermediate which is rapidly trapped by the unmasked nucleophile to form the activated ester intermediate and either a
137:
removed by washing and filtration. This approach circumvents the comparatively time-consuming isolation of the product peptide from solution after each reaction step, which would be required when using conventional solution-phase synthesis.
332:
603:
Permanent side-chain protecting groups used during Boc/benzyl SPPS are typically benzyl or benzyl-based groups. Final removal of the peptide from the solid support occurs simultaneously with side chain deprotection using anhydrous
208:, and as such usually requires 'coupling reagents' or 'activators'. A wide range of coupling reagents exist, due in part to their varying effectiveness for particular couplings, many of these reagents are commercially available.
3574:
Sieber P, Kamber B, Riniker B, Rittel W (10 December 1980). "Iodine
Oxidation of S-Trityl- and S-Acetamidomethyl-cysteine-peptides Containing Tryptophan: Conditions Leading to the Formation of Tryptophan-2-thioethers".
1783:
Hiebl, J.; Baumgartner, H.; Bernwieser, I.; Blanka, M.; Bodenteich, M.; Leitner, K.; Rio, A.; Rovenszky, F.; Alberts, D.P.; Bhatnagar, P.K.; Banyard, A.F.; Baresch, K.; Esch, P.M.; Kollmann, H.; Mayrhofer, G. (1999).
1614:
SubirΓ³s-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F (September 2009). "Oxyma: an efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion".
876:
Thanks to inline analytics, such as UV/Vis spectroscopy and the use of
Variable Bed Flow reactor (VBFR) that monitor the resin volume, on-resin aggregation can be identified and coupling efficiency can be evaluated.
3629:
Nicolaou KC, Natarajan S, Li H, Jain NF, Hughes R, Solomon ME, et al. (October 1998). "Total
Synthesis of Vancomycin Aglycon-Part 1: Synthesis of Amino Acids 4-7 and Construction of the AB-COD Ring Skeleton".
700:
Bu SPPS however. Because the liberated fluorenyl group is a chromophore, Fmoc deprotection can be monitored by UV absorbance of the reaction mixture, a strategy which is employed in automated peptide synthesizers.
805:
scheme is required. It is also sometimes used when conducting on-resin cyclic peptide formation, where the peptide is linked to the resin by a side-chain functional group. The Alloc group can be removed using
688:
protection allows for a milder deprotection scheme than used for Boc/Bzl SPPS, and this protection scheme is truly orthogonal under SPPS conditions. Fmoc deprotection utilizes a base, typically 20β50%
723:, as the fluorenyl group is much larger than the Boc group. Accordingly, prices for Fmoc amino acids were high until the large-scale piloting of one of the first synthesized peptide drugs,
2260:
Thieriet N, Alsina J, Giralt E, GuibΓ© F, Albericio F (1997). "Use of Alloc-amino acids in solid-phase peptide synthesis. Tandem deprotection-coupling reactions using neutral conditions".
161:
193:
deprotection); if each coupling were 95% efficient, the overall yield would be 25%. and adding an excess of each amino acid (between 2- and 10-fold). The minimization of amino acid
885:
Stepwise elongation, in which the amino acids are connected step-by-step in turn, is ideal for small peptides containing between 2 and 100 amino acid residues. Another method is
133:, SPPS allows the rapid assembly of a peptide chain through successive reactions of amino acid derivatives on a macroscopically insoluble solvent-swollen beaded resin support.
1118:
Jaradat DM (January 2018). "Thirteen decades of peptide synthesis: key developments in solid phase peptide synthesis and amide bond formation utilized in peptide ligation".
704:
The ability of the Fmoc group to be cleaved under relatively mild basic conditions while being stable to acid allows the use of side chain protecting groups such as Boc and
900:: unprotected peptide chains react chemoselectively in aqueous solution. A first kinetically controlled product rearranges to form the amide bond. The most common form of
2233:
2684:
Akaji K, Fujino K, Tatsumi T, Kiso Y (1993). "Total synthesis of human insulin by regioselective disulfide formation using the silyl chloride-sulfoxide method".
262:
708:
Bu that can be removed in milder acidic final cleavage conditions (TFA) than those used for final cleavage in Boc/Bzl SPPS (HF). Scavengers such as water and
451:
a C-terminal carboxylic acid or amide is desired. The Wang resin was, as of 1996, the most commonly used resin for peptides with C-terminal carboxylic acids.
3980:
370:. The identity of this anion is typically indicated by the first letter in the reagentβs acronym, although the nomenclature can be inconsistent. For example
685:
625:
545:
149:
2929:
Sletten ET, NuΓ±o M, Guthrie D, Seeberger PH (December 2019). "Real-time monitoring of solid-phase peptide synthesis using a variable bed flow reactor".
525:). This would compete with the intended peptide coupling reaction, resulting in low yield or even complete failure to synthesize the desired peptide.
188:
An important feature that has enabled the broad application of SPPS is the generation of extremely high yields in the coupling step. Highly efficient
548:
N-terminal protection, with side chain protection and a resin linkage that are acid-labile (final acidic cleavage is carried out via TFA treatment).
807:
2634:"Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot. Models for collagen catabolism by matrix-metalloproteases"
864:
Microwave-assisted peptide synthesis has been used to complete long peptide sequences with high degrees of yield and low degrees of racemization.
560:
537:
157:
145:
2894:
Gordon CP (January 2018). "The renascence of continuous-flow peptide synthesis - an abridged account of solid and solution-based approaches".
2418:
Fodor SP, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D (February 1991). "Light-directed, spatially addressable parallel chemical synthesis".
77:. Solid phase peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (
3936:
3908:
3841:
3782:
3738:
3643:
3613:
3209:
3142:
2197:
2147:
1837:
1292:
1185:
402:
moieties can exist in an N-form (guanadinium) or an O-form (uronium), but the N-form is generally more stable. Phosphonium reagents include
4068:
129:
The established method for the production of synthetic peptides in the lab is known as solid phase peptide synthesis (SPPS). Pioneered by
521:
is essential during peptide synthesis to avoid undesirable side reactions, such as self-coupling of the activated amino acid leading to (
801:
The allyloxycarbonyl (alloc) protecting group is sometimes used to protect an amino group (or carboxylic acid or alcohol group) when an
4213:
4198:
3880:
577:-butyloxycarbonyl (abbreviated 'Boc') as a temporary N-terminal Ξ±-amino protecting group. The Boc group is removed with acid, such as
482:
2755:
504:
3408:"Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: in vitro and in vivo studies in mice"
544:
during the final cleavage step (with simultaneous cleavage of the peptide from the solid support). Fmoc/tBu SPPS uses base-labile
3973:
427:
1668:
4023:
3168:"Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation"
1366:
Tickler AK, Clippingdale AB, Wade JD (August 2004). "Amyloid-beta as a "difficult sequence" in solid phase peptide synthesis".
110:
3803:
2461:
Tam JP, Wu CR, Liu W, Zhang JW (1991). "Disulfide bond formation in peptides by dimethyl sulfoxide. Scope and applications".
486:
320:
3319:
Haridas V, Sadanandan S, Dheepthi NU (September 2014). "Sortase-based bio-organic strategies for macromolecular synthesis".
1915:
Hermkens PH, Ottenheijm HC, Rees DC (1997). "Solid-phase organic reactions II: A review of the literature Nov 95 β Nov 96".
1888:
Feinberg RS, Merrifield RB (1974). "Zinc chloride-catalyzed chloromethylation of resins for solid phase peptide synthesis".
985:
solution phase steps, that purification from by-products, reagents and unconverted material is required, and that undesired
3903:. Reactivity and Structure: Concepts in Organic Chemistry, Volume 21. New York, NY: Springer Science & Business Media.
3875:. Reactivity and Structure: Concepts in Organic Chemistry, Volume 16. New York, NY: Springer Science & Business Media.
1942:
Schnolzer MA, Jones A, Alewood D, Kent SB (2007). "In Situ
Neutralization in Boc-chemistry Solid Phase Peptide Synthesis".
1744:
Albericio, Fernando; Cases, Marta; Alsina, Jordi; Triolo, Salvatore A.; Carpino, Louis A.; Kates, Steven A. (7 July 1997).
4203:
2130:
Dick F (1995). "Acid
Cleavage/Deprotection in Fmoc/tBiu Solid-Phase Peptide Synthesis". In Pennington MW, Dunn BM (eds.).
528:
Two principle protecting group schemes are typically used in solid phase peptide synthesis: so-called Boc/benzyl and Fmoc/
4154:
2379:"Large-Scale Protein Arrays Generated with Interferometric Lithography for Spatial Control of Cell-Material Interactions"
2330:"On silico peptide microarrays for high-resolution mapping of antibody epitopes and diverse protein-protein interactions"
608:
via hydrolytic cleavage. The final product is a fluoride salt which is relatively easy to solubilize. Scavengers such as
1275:
Mant CT, Chen Y, Yan Z, Popa TV, Kovacs JM, Mills JB, et al. (2007). "HPLC analysis and purification of peptides".
972:
deprotected N-terminus. Once cyclization has taken place, the peptide is cleaved from resin by acidolysis and purified.
346:-reagent can be employed These reagents have two parts: an electrophilic moiety which deoxygenates the carboxylic acid (
308:
265:(EDC) is often used for solution-phase peptide couplings as its urea byproduct can be removed by washing during aqueous
85:
of the long polypeptide chains found in the protein molecules of living organisms occurs in the opposite direction. The
1717:
Albericio F, Bofill JM, El-Faham A, Kates SA (1998). "Use of Onium Salt-Based
Coupling Reagents in Peptide Synthesis".
4188:
4142:
4123:
3966:
2105:
300:
of the activated amino acid. Racemization can be circumvented with 'racemization suppressing' additives such as the
4053:
3531:
Chow HY, Zhang Y, Matheson E, Li X (September 2019). "Ligation
Technologies for the Synthesis of Cyclic Peptides".
1977:
Beyermann M, Bienert M (1992). "Synthesis of difficult peptide sequences: A comparison of Fmoc-and BOC-technique".
246:. This reactive intermediate is attacked by the peptide N-terminal amine, forming a peptide bond. Formation of the
785:
unattainable peptides with reactive side-chains, while Z-protected amino acids are also prevented form undergoing
4058:
4003:
1025:
238:(DIC) are frequently used for amide bond formation. The reaction proceeds via the formation of a highly reactive
2711:
Pedersen SL, Tofteng AP, Malik L, Jensen KJ (March 2012). "Microwave heating in solid-phase peptide synthesis".
1652:
4033:
2577:"General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins"
1035:
951:
901:
886:
231:
177:
2857:"An optimised approach for continuous-flow solid-phase peptide synthesis utilising a rudimentary flow reactor"
2773:"Peptide synthesis. Part 8. A system for solid-phase synthesis under low pressure continuous flow conditions"
802:
4098:
1345:
1201:
1030:
475:
235:
130:
338:
To avoid epimerization through the O-acylisourea intermediate formed when using a carbodiimide reagent, an
4113:
4063:
3577:
907:
Other methods applicable for covalently linking polypeptides in aqueous solution include the use of split
600:
or thioester moeities), as treatment with base is required during the Fmoc deprotection step (see below).
4208:
4108:
551:
Both approaches, including the advantages and disadvantages of each, are outlined in more detail below.
1785:
1745:
1546:
4028:
4008:
2987:
2588:
2427:
1684:"Phosphonium- and Benzotriazolyloxy-Mediated Bond-Forming Reactions and Their Synthetic Applications"
947:
889:, in which peptide fragments are coupled. Although the former can elongate the peptide chain without
751:
578:
533:
399:
304:
164:
are increasingly being used in commercial settings to maximize the yield without sacrificing purity.
122:
727:, began in the 1990s, when market demand adjusted the relative prices of Fmoc- vs Boc- amino acids.
4043:
1475:
Valeur E, Bradley M (February 2009). "Amide bond formation: beyond the myth of coupling reagents".
1232:
Mitchell AR (2008). "Bruce Merrifield and solid-phase peptide synthesis: a historical assessment".
859:
612:
must be added to the HF in order to prevent reactive cations from generating undesired byproducts.
589:
438:
363:
266:
4161:
3497:
3989:
3556:
3388:
3344:
3107:
2663:
2557:
2203:
1959:
1257:
1143:
1097:
814:
709:
996:
The use of pentafluorophenyl esters (FDPP, PFPOH) and BOP-Cl are useful for cyclising peptides.
280:
62:
1510:
El-Faham A, Albericio F (November 2011). "Peptide coupling reagents, more than a letter soup".
1404:
El-Faham A, Albericio F (November 2011). "Peptide coupling reagents, more than a letter soup".
4193:
4083:
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4013:
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3904:
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3857:
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3778:
3761:
3734:
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3647:
3609:
3548:
3513:
3478:
3437:
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3336:
3301:
3260:
3197:
3148:
3138:
3099:
3064:
3015:
2956:
2911:
2876:
2837:
2788:
2751:
2728:
2655:
2614:
2549:
2505:
2443:
2400:
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2310:
2193:
2153:
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2087:
2052:
1870:
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1765:
1699:
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1527:
1492:
1421:
1383:
1308:
1288:
1249:
1206:
1181:
1135:
1089:
897:
846:(Trt) groups. Importantly, the NPYS group can replace the Acm PG to yield an activated thiol.
693:
605:
541:
518:
367:
3280:"Secrets of a covalent interaction for biomaterials and biotechnology: SpyTag and SpyCatcher"
3050:
2070:
Huang H, Rabenstein DL (May 1999). "A cleavage cocktail for methionine-containing peptides".
1746:"On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis"
54:
structure, ti enhance its stability, and/or modify other properties of the peptide molecule.
33:
Peptides are chemically synthesized by the condensation reaction of an activated form of the
17:
4166:
4073:
4048:
3847:
3829:
3753:
3706:
3679:
3639:
3586:
3540:
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3427:
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3291:
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2946:
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2435:
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2349:
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2328:
Price JV, Tangsombatvisit S, Xu G, Yu J, Levy D, Baechler EC, et al. (September 2012).
2300:
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2185:
2135:
2079:
2042:
2032:
1986:
1951:
1924:
1897:
1862:
1797:
1786:"Largeβscale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling"
1757:
1726:
1691:
1664:
1624:
1594:
1584:
1519:
1484:
1457:
1413:
1375:
1326:
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1079:
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927:
766:
141:
118:
90:
86:
71:
42:
2021:"Deprotection Reagents in Fmoc Solid Phase Peptide Synthesis: Moving Away from Piperidine?"
761:
Introduction of the Z protecting group from reaction with benzyl chloroformate (Z-chloride)
757:
176:
are difficult to make. Longer lengths can be accessed by using ligation approaches such as
4118:
3129:. Methods in Molecular Biology. Vol. 35. New Jersey: Humana Press. pp. 303β316.
2228:
1006:
747:
565:
1327:"Custom peptide synthesis service. HPLC refers to High Performance Liquid Chromatography"
398:(chloride) and COMU (ethyl cyano(hydroxyimino)acetate). Amidinium reagents incorporating
152:(base-labile), depending on the side chain and the protection strategy used (see below).
3793:
3757:
2991:
2750:. Methods and Principles in Medicinal Chemistry. Vol. 52 (Second ed.). Wiley.
2632:
Ottl J, Battistuta R, Pieper M, Tschesche H, Bode W, KΓΌhn K, Moroder L (November 1996).
2592:
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2134:. Methods in Molecular Biology. Vol. 35. Totowa, NJ: Humana Press. pp. 63β72.
1866:
4093:
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3852:
3821:
3432:
3407:
3406:
Rizzi A, Rizzi D, Marzola G, Regoli D, Larsen BD, Petersen JS, Calo' G (October 2002).
3255:
3230:
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3034:
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2329:
2047:
2020:
1303:
968:
923:
818:
673:
661:
654:
522:
168:
97:. This is followed by a coupling step (a protected amino acid is added) to the growing
34:
3684:
3666:
2806:
Simon MD, Heider PL, Adamo A, Vinogradov AA, Mong SK, Li X, et al. (March 2014).
2650:
2633:
2273:
1928:
1901:
1761:
596:
butyl approach when synthesizing peptides containing base-sensitive moieties (such as
257:
DIC is particularly useful for SPPS since as a liquid it is easily dispensed, and the
4182:
4103:
3701:
3560:
3010:
2975:
2951:
2561:
2083:
1990:
1801:
1599:
1062:
Isidro-Llobet A, Alvarez M, Albericio F (June 2009). "Amino acid-protecting groups".
935:
774:
741:
680:
such as the piperidine (which is in large excess), or potentially the released amine.
642:
573:
Before the advent of SPPS, solution methods for chemical peptide synthesis relied on
359:
3392:
3348:
2667:
2207:
1963:
1261:
1101:
817:, protecting groups sometimes termed "lithographic" are used, which are amenable to
180:, where two shorter fully deprotected synthetic peptides can be joined in solution.
4018:
3111:
2224:
1653:"The Uronium/Guanidinium Peptide Coupling Reagents: Finally the True Uronium Salts"
1147:
1012:
890:
786:
781:
720:
677:
597:
316:
297:
227:
194:
114:
82:
2019:
Luna OF, Gomez J, CΓ‘rdenas C, Albericio F, Marshall SH, GuzmΓ‘n F (November 2016).
362:
by-product. These cationic reagents have non-coordinating counteranions such as a
3926:
3898:
3870:
3833:
3166:
Flood DT, Hintzen JC, Bird MJ, Cistrone PA, Chen JS, Dawson PE (September 2018).
2305:
2288:
1589:
842:-butyl (But), 3-nitro-2-pyridine sulfenyl (NPYS), 2-pyridine-sulfenyl (Pyr), and
3644:
10.1002/(SICI)1521-3773(19981016)37:19<2708::AID-ANIE2708>3.0.CO;2-E
3544:
3134:
2488:
Sieber P, Kamber B, Hartmann A, JΓΆhl A, Riniker B, Rittel W (January 1977). "".
1284:
943:
822:
780:
This methodology was first used in the synthesis of oligopeptides by Zervas and
770:
724:
464:
403:
343:
323:(Oxyma), an additive for carbodiimide coupling, acts as an alternative to HOAt.
288:
216:
38:
3296:
3279:
2980:
Proceedings of the National Academy of Sciences of the United States of America
2600:
2139:
950:, improve peptide stability and inhibit enzymatic degradation without altering
630:
319:, which subsequently reacts with the peptide to form the desired peptide bond.
2189:
2037:
1955:
1461:
1448:
Montalbetti CA, Falque V (2005). "Amide bond formation and peptide coupling".
1131:
990:
939:
746:
The (Z) group is another carbamate-type amine protecting group, discovered by
689:
638:
592:
during synthesis. In addition, Boc/benzyl SPPS may be preferred over the Fmoc/
94:
78:
74:
3798:. Practical Approach Series, Issue 222. Oxford, UK: Oxford University Press.
3590:
3517:
3246:
2880:
2792:
2501:
2404:
2246:
1809:
1769:
1703:
1379:
1204:(1963). "Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide".
144:
on its N-terminus and side chain using appropriate protecting groups such as
3376:
3000:
2439:
1279:. Methods in Molecular Biology. Vol. 386. Humana Press. pp. 3β55.
664:
is also generated. This reaction is able to occur due to the acidity of the
650:
415:
3861:
3651:
3552:
3482:
3441:
3423:
3384:
3340:
3332:
3305:
3264:
3201:
3183:
3103:
3068:
2960:
2915:
2841:
2823:
2732:
2618:
2553:
2363:
2314:
2106:"Cleavage Cocktails; Reagent B; Reagent H; Reagent K; Reagent L; Reagent R"
2091:
2056:
1695:
1636:
1628:
1572:
1531:
1496:
1425:
1387:
1312:
1253:
1139:
1093:
540:
protection alongside side chain protection that is removed using anhydrous
3765:
3152:
3019:
2659:
2447:
2395:
2378:
2157:
1874:
331:
50:
usefulness in large-scale production of peptides for industrial purposes.
3710:
2784:
2772:
2528:"Cysteine protecting groups: applications in peptide and protein science"
2509:
986:
919:
669:
665:
646:
301:
2697:
2474:
1218:
821:
at a particular wavelength of light, and so which can be removed during
2942:
2907:
2872:
2856:
2724:
2544:
2527:
1669:
10.1002/1521-3773(20020201)41:3<441::AID-ANIE441>3.0.CO;2-N
912:
904:
uses a peptide thioester that reacts with a terminal cysteine residue.
489: in this section. Unsourced material may be challenged and removed.
442:
Cross-linked polystyrene is the most common solid support used in SPPS.
339:
173:
98:
2976:"Expressed protein ligation: a general method for protein engineering"
1730:
1523:
1417:
1245:
1084:
1075:
330:
261:
byproduct is easily washed away. Conversely, the related carbodiimide
140:
Each amino acid to be coupled to the peptide chain N-terminus must be
3958:
3509:
3095:
1488:
931:
908:
843:
609:
198:
3699:
Baker R, Castro JL (1989). "The total synthesis of (+)-macbecin I".
3473:
3456:
2345:
3733:(2nd ed.). Rockford, IL: Pierce Chemical Company. p. 91.
2855:
Spare LK, Laude V, Harman DG, Aldrich-Wright JR, Gordon CP (2018).
756:
629:
564:
437:
411:
407:
287:
279:
271:
220:
215:
205:
189:
67:
3752:. Vol. 57. Palo Alto, CA: Annual Reviews. pp. 957β989.
3082:
Kent SB (February 2009). "Total chemical synthesis of proteins".
588:
The Boc/Bzl approach retains its usefulness in reducing peptide
395:
391:
387:
383:
355:
258:
254:
proceeds fastest in non-polar solvents such as dichloromethane.
251:
243:
106:
102:
3962:
3748:
Kent SB (1988). "Chemical Synthesis of Peptides and Proteins".
1853:
Kent SB (1988). "Chemical synthesis of peptides and proteins".
1547:"CarboMAX - Enhanced Peptide Coupling at Elevated Temperatures"
272:
2575:
Laps S, Atamleh F, Kamnesky G, Sun H, Brik A (February 2021).
2231:(1932). "Γber ein allgemeines Verfahren der Peptid-Synthese".
458:
66:
Scheme of solid phase peptides synthesis (SPPS) on polymeric
2289:"Combinatorial solid phase peptide synthesis and bioassays"
447:
takes place inside the swollen pores of the solid support.
204:
Amide bond formation between an amine and carboxylic acid
3667:"Synthetic studies of 14-membered cyclopeptide alkaloids"
3365:
The Journal of Pharmacology and Experimental Therapeutics
896:
A new development for producing longer peptide chains is
517:
As described above, the use of N-terminal and side chain
3795:
Fmoc Solid Phase Peptide Synthesis: A Practical Approach
1178:
Fmoc Solid Phase Peptide Synthesis: A Practical Approach
813:
For special applications like synthetic steps involving
1823:
1821:
1819:
1682:
Mansour, Tarek; Bardhan, Sujata; Wan, Zhao-Kui (2010).
750:
in the early 1930s and usually added via reaction with
3502:
Journal of the Chemical Society, Perkin Transactions 1
3496:
Lambert JN, Mitchell JP, Roberts KD (1 January 2001).
3039:
Annual Review of Biophysics and Biomolecular Structure
2777:
Journal of the Chemical Society, Perkin Transactions 1
1010:
in 1882 and the first free peptide was synthesised by
197:
during coupling is also of vital importance to avoid
3931:. Boca Raton, FL: CRC Press / Taylor & Frances.
2287:
Shin DS, Kim DH, Chung WJ, Lee YS (September 2005).
3996:
3775:
Solid Phase peptide synthesis: a practical approach
3606:Linker Strategies in Solid-Phase Organic Synthesis
3172:Angewandte Chemie International Edition in English
2526:Spears RJ, McMahon C, Chudasama V (October 2021).
1832:(1 ed.). Boca Raton: CRC Press. p. 848.
1277:Peptide Characterization and Application Protocols
418:by-product, whereas phosphonium reagents are not.
296:Carbodiimide activation opens the possibility for
3210:"Peptide Thioesters for Native Chemical Ligation"
1057:
1055:
1053:
1051:
1443:
1441:
1439:
1437:
1435:
532:butyl approaches. The Boc/Bzl strategy utilizes
382:BTU is a tetrafluoroborate salt. In addition to
3457:"The cyclization of peptides and depsipeptides"
1004:The first protected peptide was synthesised by
946:-like structure. This can potentially increase
938:(Glun); (LysGlu)n) that is incorporated at the
2377:Hedberg-Dirk EL, Martinez UA (8 August 2010).
2234:Berichte der deutschen chemischen Gesellschaft
793:more commonly used for side chain protection.
3974:
3229:Aranko AS, Wlodawer A, IwaΓ― H (August 2014).
2748:Microwaves in Organic and Medicinal Chemistry
2293:Journal of Biochemistry and Molecular Biology
1399:
1397:
868:Continuous flow solid-phase peptide synthesis
263:1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
8:
911:, spontaneous isopeptide bond formation and
668:proton, resulting from stabilization of the
3608:. John Wiley & Sons. pp. 135β137.
3235:Protein Engineering, Design & Selection
3127:Peptide synthesis via fragment condensation
3033:Nilsson BL, Soellner MB, Raines RT (2005).
765:It is removed under harsh conditions using
637:Treatment of the Fmoc-protected amine with
626:Fluorenylmethyloxycarbonyl protecting group
3981:
3967:
3959:
3278:Reddington SC, Howarth M (December 2015).
3851:
3683:
3472:
3431:
3295:
3254:
3191:
3058:
3009:
2999:
2950:
2831:
2746:Kappe CO, Stadler A, Dallinger D (2012).
2649:
2608:
2543:
2394:
2353:
2304:
2046:
2036:
1598:
1588:
1302:
1083:
505:Learn how and when to remove this message
3051:10.1146/annurev.biophys.34.040204.144700
2974:Muir TW, Sondhi D, Cole PA (June 1998).
2686:Journal of the American Chemical Society
1830:Solid-Phase Synthesis: A Practical Guide
1171:
1169:
1167:
1165:
1163:
1161:
1159:
1157:
808:tetrakis(triphenylphosphine)palladium(0)
653:, which decomposes into carbon dioxide (
649:ring system. This leads to release of a
376:BTU is a hexafluorophosphate salt while
61:
3231:"Nature's recipe for splitting inteins"
2679:
2677:
1657:Angewandte Chemie International Edition
1047:
918:In order to optimize synthesis of long
829:Regioselective disulfide bond formation
641:results in proton abstraction from the
37:of one alpha-amino acid with the alpha-
2008:. Oxford, UK: Oxford University Press.
561:Tert-butyloxycarbonyl protecting group
2521:
2519:
2219:
2217:
2173:
2171:
2169:
2167:
315:-acylisourea intermediate to form an
7:
4149:
3826:Current Protocols in Protein Science
2896:Organic & Biomolecular Chemistry
2861:Reaction Chemistry & Engineering
2808:"Rapid flow-based peptide synthesis"
1113:
1111:
854:Microwave-assisted peptide synthesis
773:, or milder conditions of catalytic
585:during the basic coupling reaction.
487:adding citations to reliable sources
3822:"Introduction to peptide synthesis"
3758:10.1146/annurev.bi.57.070188.004521
3284:Current Opinion in Chemical Biology
1867:10.1146/annurev.bi.57.070188.004521
1573:"Evolution of Amide Bond Formation"
1344:Lundemann-Hombourger O (May 2013).
41:of a second amino acid. Reversible
3498:"The synthesis of cyclic peptides"
350:) and masked nucleophilic moiety (
311:(HOAt). These reagents attack the
25:
3900:The Practice of Peptide Synthesis
3897:Bodanszky M, Bodanszky A (2013).
930:. The simple pre-sequence (e.g.
292:Neighbouring group effect of HOAt
4160:
4148:
4137:
4136:
3773:Atherton E, Sheppard RC (1989).
3035:"Chemical synthesis of proteins"
2084:10.1034/j.1399-3011.1999.00059.x
2006:Amino Acid and Peptide Synthesis
1802:10.1034/j.1399-3011.1999.00089.x
463:
428:propanephosphonic acid anhydride
422:Propanephosphonic acid anhydride
113:) are employed to help form the
3872:Principles of Peptide Synthesis
3412:British Journal of Pharmacology
2771:Dryland A, Sheppard RC (1986).
2072:The Journal of Peptide Research
1790:The Journal of Peptide Research
474:needs additional citations for
327:Amidinium and phosphonium salts
101:chain. Coupling reagents (e.g.
3928:Chemistry of Peptide Synthesis
3792:Chan W, White P, eds. (2000).
3777:. Oxford, England: IRL Press.
1571:JoulliΓ© MM, Lassen KM (2010).
797:Alloc and miscellaneous groups
390:other common reagents include
321:Ethyl cyanohydroxyiminoacetate
223:bond formation using DIC/HOBt.
201:in the final peptide product.
27:Chemical synthesis of peptides
1:
3828:. Chapter 18: 18.1.1β18.1.9.
3750:Annual Review of Biochemistry
3731:Solid phase peptide synthesis
3729:Stewart JM, Young JD (1984).
3685:10.1016/S0040-4039(98)01589-5
3125:Nyfeler R (7 November 1994).
2651:10.1016/S0014-5793(96)01212-4
2274:10.1016/S0040-4039(97)01690-0
2181:The Chemistry of Polypeptides
1929:10.1016/S0040-4020(97)00279-2
1902:10.1016/S0040-4020(01)97575-1
1855:Annual Review of Biochemistry
1762:10.1016/S0040-4039(97)01011-3
1617:Chemistry: A European Journal
1353:Speciality Chemicals Magazine
309:1-hydroxy-7-aza-benzotriazole
18:Solid phase peptide synthesis
3834:10.1002/0471140864.ps1801s26
3665:East SP, JoulliΓ© MM (1998).
2306:10.5483/BMBRep.2005.38.5.517
2178:Katsoyannis PG, ed. (1973).
1991:10.1016/0040-4039(92)80014-B
1590:10.3998/ark.5550190.0011.816
942:of the peptide to induce an
922:, a method was developed in
4124:Volume combustion synthesis
3820:Fields GB (February 2002).
3604:Scott P (13 October 2009).
3545:10.1021/acs.chemrev.8b00657
2132:Peptide Synthesis Protocols
1944:Int. J. Peptide Res. Therap
1368:Protein and Peptide Letters
1285:10.1007/978-1-59745-430-8_1
635:Cleavage of the Fmoc group.
4230:
4054:Enantioselective synthesis
3461:Journal of Peptide Science
3297:10.1016/j.cbpa.2015.10.002
2601:10.1038/s41467-021-21209-0
2184:. New York: Plenum Press.
1176:Chan WC, White PD (2000).
881:Synthesizing long peptides
857:
739:
676:by-product can react with
623:
558:
4214:Amide synthesis reactions
4199:Peptide coupling reagents
4132:
4059:Fully automated synthesis
4004:Artificial gene synthesis
3455:Davies JS (August 2003).
3135:10.1385/0-89603-273-6:303
2952:21.11116/0000-0005-3E5F-D
2190:10.1007/978-1-4613-4571-8
2038:10.3390/molecules21111542
1956:10.1007/s10989-006-9059-7
1600:2027/spo.5550190.0011.816
1462:10.1016/j.tet.2005.08.031
1346:"The ideal peptide plant"
1132:10.1007/s00726-017-2516-0
1026:Oligonucleotide synthesis
569:Cleavage of the Boc group
455:Protecting groups schemes
184:Peptide coupling reagents
4034:Custom peptide synthesis
3591:10.1002/hlca.19800630826
3084:Chemical Society Reviews
2713:Chemical Society Reviews
2532:Chemical Society Reviews
2502:10.1002/hlca.19770600105
2383:Journal of Nanomaterials
2247:10.1002/cber.19320650722
2140:10.1385/0-89603-273-6:63
1545:Singh S (January 2018).
1477:Chemical Society Reviews
1380:10.2174/0929866043406986
1036:Bailey peptide synthesis
952:pharmacological activity
902:native chemical ligation
232:dicyclohexylcarbodiimide
178:native chemical ligation
89:is usually done using a
3377:10.1124/jpet.105.083436
3001:10.1073/pnas.95.12.6705
2931:Chemical Communications
2440:10.1126/science.1990438
1031:Clicked peptide polymer
993:formation is involved.
803:orthogonal deprotection
731:Other protecting groups
305:1-hydroxy-benzotriazole
236:diisopropylcarbodiimide
131:Robert Bruce Merrifield
4114:Solvothermal synthesis
4064:Hydrothermal synthesis
3578:Helvetica Chimica Acta
3424:10.1038/sj.bjp.0704894
3333:10.1002/cbic.201402013
3247:10.1093/protein/gzu028
3184:10.1002/anie.201805191
2824:10.1002/cbic.201300796
2490:Helvetica Chimica Acta
1696:10.1055/s-0029-1219820
1629:10.1002/chem.200900614
954:or profile of action.
762:
684:The use of N-terminal
681:
660:) and the free amine.
570:
443:
335:
293:
285:
277:
224:
126:
4109:Solid-phase synthesis
2581:Nature Communications
980:Off-resin cyclization
887:fragment condensation
825:types of operations.
760:
633:
568:
441:
334:
291:
283:
275:
219:
65:
58:Solid phase synthesis
4204:Biochemistry methods
4029:Convergent synthesis
4009:Biomimetic synthesis
3925:Benoiton NL (2016).
3869:Bodanszky M (2012).
3711:10.1039/C39890000378
2785:10.1039/p19860000125
1828:Albericio F (2000).
963:On resin cyclization
948:biological half-life
752:benzyl chloroformate
579:trifluoroacetic acid
483:improve this article
400:hydroxybenzotriazole
4044:Divergent synthesis
3216:. 9 September 2018.
3178:(36): 11634β11639.
2992:1998PNAS...95.6705M
2937:(97): 14598β14601.
2698:10.1021/ja00077a043
2692:(24): 11384β11392.
2593:2021NatCo..12..870L
2538:(19): 11098β11155.
2475:10.1021/ja00017a044
2432:1991Sci...251..767F
2396:10.1155/2010/176750
2262:Tetrahedron Letters
1979:Tetrahedron Letters
1750:Tetrahedron Letters
1456:(46): 10827β10852.
1219:10.1021/ja00897a025
1180:. Oxford, UK: OUP.
860:microwave chemistry
815:protein microarrays
536:-labile N-terminal
364:hexafluorophosphate
167:SPPS is limited by
158:reversed-phase HPLC
4189:Chemical synthesis
3990:Chemical synthesis
3539:(17): 9971β10001.
2943:10.1039/C9CC08421E
2908:10.1039/C7OB02759A
2873:10.1039/C8RE00190A
2725:10.1039/C1CS15214A
2545:10.1039/D1CS00271F
763:
736:Benzyloxy-carbonyl
710:triisopropylsilane
682:
672:anion formed. The
571:
444:
426:Since late 2000s,
336:
294:
286:
278:
225:
127:
117:. The final
4176:
4175:
4089:Peptide synthesis
4084:Organic synthesis
4079:One-pot synthesis
4014:Bioretrosynthesis
3938:978-1-4200-2769-3
3910:978-3-642-96835-8
3843:978-0-471-14086-3
3784:978-0-19-963067-7
3740:978-0-935940-03-9
3678:(40): 7211β7214.
3672:Tetrahedron Lett.
3638:(19): 2708β2714.
3632:Angewandte Chemie
3615:978-0-470-74905-0
3327:(13): 1857β1867.
3144:978-0-89603-273-6
2986:(12): 6705β6710.
2469:(17): 6657β6662.
2426:(4995): 767β773.
2268:(41): 7275β7278.
2199:978-1-4613-4571-8
2149:978-1-59259-522-8
1985:(26): 3745β3748.
1923:(16): 5643β5678.
1896:(17): 3209β3212.
1839:978-0-8247-0359-2
1756:(27): 4853β4856.
1731:10.1021/jo980807y
1725:(26): 9678β9683.
1623:(37): 9394β9403.
1524:10.1021/cr100048w
1518:(11): 6557β6602.
1418:10.1021/cr100048w
1412:(11): 6557β6602.
1294:978-1-59745-430-8
1246:10.1002/bip.20925
1213:(14): 2149β2154.
1207:J. Am. Chem. Soc.
1187:978-0-19-963724-9
1076:10.1021/cr800323s
989:can be formed if
928:peptide sequences
898:chemical ligation
606:hydrogen fluoride
542:hydrogen fluoride
519:protecting groups
515:
514:
507:
368:tetrafluoroborate
148:(acid-labile) or
121:is followed by a
43:protecting groups
16:(Redirected from
4221:
4164:
4152:
4151:
4140:
4139:
4074:Mechanosynthesis
4049:Electrosynthesis
3983:
3976:
3969:
3960:
3949:
3947:
3945:
3921:
3919:
3917:
3893:
3891:
3889:
3865:
3855:
3816:
3814:
3812:
3788:
3769:
3744:
3715:
3714:
3696:
3690:
3689:
3687:
3662:
3656:
3655:
3626:
3620:
3619:
3601:
3595:
3594:
3585:(8): 2358β2363.
3571:
3565:
3564:
3533:Chemical Reviews
3528:
3522:
3521:
3510:10.1039/B001942I
3493:
3487:
3486:
3476:
3452:
3446:
3445:
3435:
3403:
3397:
3396:
3359:
3353:
3352:
3316:
3310:
3309:
3299:
3275:
3269:
3268:
3258:
3226:
3220:
3217:
3205:
3195:
3163:
3157:
3156:
3122:
3116:
3115:
3096:10.1039/B700141J
3079:
3073:
3072:
3062:
3030:
3024:
3023:
3013:
3003:
2971:
2965:
2964:
2954:
2926:
2920:
2919:
2891:
2885:
2884:
2852:
2846:
2845:
2835:
2803:
2797:
2796:
2768:
2762:
2761:
2743:
2737:
2736:
2719:(5): 1826β1844.
2708:
2702:
2701:
2681:
2672:
2671:
2653:
2629:
2623:
2622:
2612:
2572:
2566:
2565:
2547:
2523:
2514:
2513:
2485:
2479:
2478:
2463:J. Am. Chem. Soc
2458:
2452:
2451:
2415:
2409:
2408:
2398:
2374:
2368:
2367:
2357:
2340:(9): 1434β1440.
2325:
2319:
2318:
2308:
2284:
2278:
2277:
2257:
2251:
2250:
2241:(7): 1192β1201.
2221:
2212:
2211:
2175:
2162:
2161:
2127:
2121:
2120:
2118:
2116:
2102:
2096:
2095:
2067:
2061:
2060:
2050:
2040:
2016:
2010:
2009:
2004:Jones J (1992).
2001:
1995:
1994:
1974:
1968:
1967:
1939:
1933:
1932:
1912:
1906:
1905:
1885:
1879:
1878:
1850:
1844:
1843:
1825:
1814:
1813:
1780:
1774:
1773:
1741:
1735:
1734:
1714:
1708:
1707:
1690:(8): 1143β1169.
1679:
1673:
1672:
1647:
1641:
1640:
1611:
1605:
1604:
1602:
1592:
1568:
1562:
1561:
1551:
1542:
1536:
1535:
1512:Chemical Reviews
1507:
1501:
1500:
1489:10.1039/B701677H
1472:
1466:
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1445:
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1429:
1406:Chemical Reviews
1401:
1392:
1391:
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1334:
1333:. November 2021.
1331:Remetide Biotech
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1105:
1087:
1070:(6): 2455β2504.
1064:Chemical Reviews
1059:
967:Peptides can be
719:Bu SPPS is less
510:
503:
499:
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467:
459:
21:
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4119:Total synthesis
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3722:Further reading
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3474:10.1002/psc.491
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3214:Chemistry Views
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2346:10.1038/nm.2913
2334:Nature Medicine
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2018:
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1109:
1061:
1060:
1049:
1044:
1022:
1007:Theodor Curtius
1002:
982:
965:
960:
958:Cyclic peptides
926:for converting
883:
870:
862:
856:
831:
799:
748:Leonidas Zervas
744:
738:
733:
721:atom-economical
658:
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622:
563:
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169:reaction yields
60:
28:
23:
22:
15:
12:
11:
5:
4227:
4225:
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4216:
4211:
4206:
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4174:
4173:
4171:
4170:
4158:
4146:
4133:
4130:
4129:
4127:
4126:
4121:
4116:
4111:
4106:
4101:
4099:Retrosynthesis
4096:
4094:Radiosynthesis
4091:
4086:
4081:
4076:
4071:
4066:
4061:
4056:
4051:
4046:
4041:
4039:Direct process
4036:
4031:
4026:
4024:Chemosynthesis
4021:
4016:
4011:
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4000:
3998:
3994:
3993:
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3955:External links
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3882:978-3642967634
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3717:
3716:
3705:(6): 378β381.
3691:
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3621:
3614:
3596:
3566:
3523:
3504:(5): 471β484.
3488:
3467:(8): 471β501.
3447:
3418:(3): 369β374.
3398:
3371:(2): 652β660.
3354:
3311:
3270:
3241:(8): 263β271.
3221:
3219:
3218:
3158:
3143:
3117:
3090:(2): 338β351.
3074:
3025:
2966:
2921:
2902:(2): 180β196.
2886:
2867:(6): 875β882.
2847:
2818:(5): 713β720.
2798:
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2738:
2703:
2673:
2624:
2567:
2515:
2480:
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2299:(5): 517β525.
2279:
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2198:
2163:
2148:
2122:
2097:
2078:(5): 548β553.
2062:
2011:
1996:
1969:
1950:(1β2): 31β44.
1934:
1907:
1880:
1861:(1): 957β989.
1845:
1838:
1815:
1775:
1736:
1709:
1674:
1663:(3): 441β445.
1642:
1606:
1583:(8): 189β250.
1563:
1537:
1502:
1483:(2): 606β631.
1467:
1431:
1393:
1374:(4): 377β384.
1358:
1336:
1318:
1293:
1267:
1240:(3): 175β184.
1224:
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1038:
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924:Medicon Valley
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827:
819:photochemistry
798:
795:
737:
734:
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674:dibenzofulvene
662:Dibenzofulvene
656:
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614:
559:Main article:
556:
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523:polymerization
513:
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979:
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936:Glutamic Acid
933:
929:
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772:
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742:Carboxybenzyl
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643:methine group
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598:depsipeptides
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472:This section
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360:phosphoramide
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228:Carbodiimides
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199:epimerization
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40:
36:
31:
19:
4209:Biochemistry
4165:
4153:
4141:
4088:
4019:Biosynthesis
3942:. Retrieved
3927:
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115:peptide bond
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3321:ChemBioChem
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987:oligomers
666:fluorenyl
651:carbamate
647:fluorenyl
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416:guanidino
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4194:Peptides
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230:such as
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