162:(ICK) scaffold. Generally, ICK peptides are most prominently present in the venom of snails and spiders. These peptides usually function as gating modifier toxins affecting the gating and kinetic properties of voltage-gated ion channels. The ICK fold is characterized by two β-strands composing the polypeptide backbone from which two disulfide bonds originate. These disulfide bonds and the polypeptide backbone form a ring structure, which is innervated by a third sulfide bond creating a
190:(NaSpTx) family 1, because it accommodates the same cysteine structure and ICK scaffold. Toxins of NaSpTx family 1 are characterized by containing the following motif present in the amino acid sequence of the toxins: (R/K)X(R/K)WCK. The amino acid sequence of Cl6a contains the NaSpTx family 1 motif KHKWCK. Cl6a highly resembles a similar sequence with other spider peptide toxins. For instance, the amino acid sequence of Cl6a shows 67% sequence similarity with
330:
Since Cl6a contains the ICK motif, which is interestingly resistant to proteases, this peptide toxin could have further therapeutic implications. ICK peptides are stable in the human body for multiple days and demonstrate half-lives larger than 12 hours in a simulated gastric environment. Altogether,
273:
1.7 channels by binding to site 4 of domain II (DII S3-S4), which contains acidic residues. Cl6a acquires a positively charged surface that interacts with the acidic residues of site 4. Subsequently, the DII S3-S4 voltage sensor becomes trapped. Hereby, the channel is less sensitive to changes in the
486:
Shields, S. D., Deng, L., Reese, R. M., Dourado, M., Tao, J., Foreman, O., Chang, J. H., & Hackos, D. H. (2018). Insensitivity to Pain upon Adult-Onset
Deletion of Nav1.7 or Its Blockade with Selective Inhibitors. The Journal of Neuroscience, 38(47), 10180–10201.
294:
of Cl6a is 11.00 ± 2.5 nM. Generally, spider peptide toxins can incapacitate prey and hereby promote successful predation. In combination with the irreversible properties of Cl6a, this spider peptide toxin could indirectly be lethal to its prey.
386:
Wirth, V. von & Striffler, B. F. (2005). Neue
Erkenntnisse zur Vogelspinnen - Unterfamilie Ornithoctoninae, mit Beschreibung von Ornithoctonus aureotibialis sp. n. und Haplopelma longipes sp. n. (Araneae, Theraphosidae). Arthropoda 13(2):
469:
Zhang, Y., Yang, Q., Zhang, Q., Peng, D., Chen, M., Liang, S., Zhou, X., & Liu, Z. (2018). Engineering Gain-of-Function
Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNaV1.7 Sodium Channel. Toxins, 10(9), 358.
369:
Zhang, Q., Si, Y., Yang, L., Wang, L., Peng, S., Chen, Y., Chen, M., Zhou, X., & Liu, Z. (2020). Two Novel
Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels. Toxins, 12(9), 529.
519:
Berrouet, C., Dorilas, N., Rejniak, K. A., & Tuncer, N. (2020). Comparison of Drug
Inhibitory Effects (IC50) in Monolayer and Spheroid Cultures. Bulletin of Mathematical Biology, 82(6).
307:
1.7 channels, which are known to be critically involved in peripheral pain regulation. Other spider peptide toxins like HNTX-III and GpTx1 cause reversible inhibition of Na
154:
Cl6a is a 33 amino acid residue peptide toxin with a molecular weight of 3775.6 Dalton. Its molecular structure encompasses six cysteine residues, which demonstrate three
431:
Saez, N. J., Senff, S., Jensen, J. E., Er, S. Y., Herzig, V., Rash, L. D., & King, G. F. (2010). Spider-Venom
Peptides as Therapeutics. Toxins, 2(12), 2851–2871.
408:
Zhu, S., Darbon, H., Dyason, K., Verdonck, F., & Tytgat, J. (2003). Evolutionary origin of inhibitor cystine knot peptides. The FASEB Journal, 17(12), 1765–1767.
503:
Dib-Hajj, S. D., Yang, Y., Black, J. A., & Waxman, S. G. (2013). The Na V 1.7 sodium channel: from molecule to man. Nature
Reviews Neuroscience, 14(1), 49–62.
127:, which was first described by von Wirth and Striffler in 2005. This spider lives in multiple Southeast Asian countries such as Thailand, Cambodia and Laos.
331:
this implies that the ICK motif of Cl6a could contribute to the delivery of certain therapeutic agents to a specific location in the human body.
274:
membrane voltage. As a consequence, the inward sodium current is not initiated. Consequently, there will be a decrease in neuronal excitability.
535:
Neff, R. A., & Wickenden, A. D. (2021). Selective
Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides. Channels, 15(1), 179–193.
450:
Craik, D. J., Daly, N. L., & Waine, C. (2001). The cystine knot motif in toxins and implications for drug design. Toxicon, 39(1), 43–60.
166:. This comprises an extraordinarily stable protein structure, which is resistant to heat denaturation, extreme pH environments and
315:
1.7 channel activity. Therefore, this spider peptide toxin is a potential therapeutic target by obtaining prolonged blockage of Na
207:
179:
37:
557:
536:
520:
504:
488:
471:
451:
432:
409:
371:
246:
123:
28:
567:
159:
562:
242:
269:
1.7 peak currents with a slow onset of action. Cl6a alters the current-voltage relationship of Na
551:
257:
free nerve endings and more centrally in the superficial lamina of the spinal cord.
187:
133:
33:
492:
540:
455:
239:
191:
167:
195:
163:
524:
327:
1.5 currents, which are involved in skeletal and cardiac muscle functioning.
254:
155:
138:
396:
Natural
History Museum Bern. (2019). NMBE - World Spider Catalog. Nmbe.ch.
475:
375:
436:
413:
26:, is a 33-residue peptide toxin extracted from the venom of the spider
41:
508:
311:
1.7 channels. However, Cl6a induces irreversible inhibition of Na
287:
286:
1.7 channels, which are involved in peripheral pain relief. The
397:
121:Cl6a is a peptide extracted from the venom of the
319:1.7 channels. Nonetheless, Cl6a also inhibits Na
465:
463:
446:
444:
265:Cl6a induces an irreversible inhibition of Na
8:
427:
425:
423:
421:
365:
363:
48:), thereby causing sustained reduction of Na
361:
359:
357:
355:
353:
351:
349:
347:
345:
343:
137:, which is a genus of the southeast Asian
54:
288:half-maximal inhibitory concentration (IC
230:1.7) with the highest affinity against Na
303:Cl6a exhibits a high affinity against Na
32:. The toxin acts as an inhibitor of the
339:
7:
206:Cl6a is a selective antagonist of
100:ACKGVFDPCTPGKNECCPNRVCSDKHKWCKWKI
14:
210:. It targets TTX-S channels (Na
238:1.7 channels are expressed in
1:
208:voltage-gated sodium channels
253:1.7 channels are located in
180:voltage-gated sodium channel
38:voltage-gated sodium channel
584:
282:Cl6a selectively blocks Na
247:olfactory sensory neurons
194:(HNTX) III and 97% with
245:(DRG), sympathetic and
158:bonds that assemble an
69:Cyriopagopus longipepes
160:inhibitor cystine knot
80:Spider peptide toxins
129:Cyriopagopus longipes
124:Cyriopagopus longipes
29:Cyriopagopus longipes
243:dorsal root ganglion
178:Cl6a belongs to the
131:originates from the
117:Etymology and Source
174:Family and homology
96:Amino acid sequence
59:
36:-sensitive (TTX-S)
558:Ion channel toxins
55:
114:
113:
575:
543:
533:
527:
517:
511:
501:
495:
484:
478:
467:
458:
448:
439:
429:
416:
406:
400:
394:
388:
384:
378:
367:
234:1.7 channels. Na
106:Molecular weight
90:NaSpTx family 1
60:
22:, also known as
583:
582:
578:
577:
576:
574:
573:
572:
548:
547:
546:
534:
530:
518:
514:
502:
498:
485:
481:
468:
461:
449:
442:
430:
419:
407:
403:
395:
391:
385:
381:
368:
341:
337:
326:
322:
318:
314:
310:
306:
301:
299:Therapeutic use
291:
285:
280:
272:
268:
263:
252:
237:
233:
229:
225:
221:
217:
213:
204:
185:
176:
152:
147:
119:
51:
45:
17:
12:
11:
5:
581:
579:
571:
570:
565:
560:
550:
549:
545:
544:
528:
512:
496:
479:
459:
440:
417:
401:
389:
379:
338:
336:
333:
324:
320:
316:
312:
308:
304:
300:
297:
289:
283:
279:
276:
270:
266:
262:
261:Mode of action
259:
250:
235:
231:
227:
223:
219:
215:
211:
203:
200:
183:
175:
172:
151:
148:
146:
143:
118:
115:
112:
111:
108:
102:
101:
98:
92:
91:
88:
82:
81:
78:
72:
71:
66:
52:1.7 currents.
49:
43:
15:
13:
10:
9:
6:
4:
3:
2:
580:
569:
568:Spider toxins
566:
564:
561:
559:
556:
555:
553:
541:
538:
532:
529:
525:
522:
516:
513:
509:
506:
500:
497:
493:
490:
483:
480:
476:
473:
466:
464:
460:
456:
453:
447:
445:
441:
437:
434:
428:
426:
424:
422:
418:
414:
411:
405:
402:
398:
393:
390:
383:
380:
376:
373:
366:
364:
362:
360:
358:
356:
354:
352:
350:
348:
346:
344:
340:
334:
332:
328:
298:
296:
293:
277:
275:
260:
258:
256:
248:
244:
241:
209:
201:
199:
197:
193:
189:
181:
173:
171:
169:
165:
161:
157:
149:
144:
142:
140:
136:
135:
130:
126:
125:
116:
109:
107:
104:
103:
99:
97:
94:
93:
89:
87:
84:
83:
79:
77:
74:
73:
70:
67:
65:
62:
61:
58:
53:
47:
39:
35:
31:
30:
25:
21:
531:
515:
499:
482:
404:
392:
382:
329:
302:
281:
264:
205:
188:spider toxin
186:)-targeting
177:
153:
134:Cyriopagopus
132:
128:
122:
120:
105:
95:
85:
76:Super family
75:
68:
63:
56:
34:tetrodotoxin
27:
23:
19:
18:
563:Neurotoxins
240:nociceptive
192:Hainantoxin
168:proteolysis
20:μ-THTX-Cl6a
552:Categories
335:References
323:1.4 and Na
226:1.6 and Na
198:(HWTX) I.
196:huwentoxin
164:pseudoknot
110:3775.6 Da
255:epidermal
156:disulfide
150:Structure
145:Chemistry
139:tarantula
278:Toxicity
64:Organism
222:1.4, Na
218:1.3, Na
214:1.2, Na
202:Target
86:Family
387:2-27.
16:Toxin
249:. Na
57:Cl6a
24:Cl6a
537:DOI
521:DOI
505:DOI
489:DOI
472:DOI
452:DOI
433:DOI
410:DOI
372:DOI
182:(Na
46:1.7
554::
462:^
443:^
420:^
342:^
290:50
170:.
141:.
42:Na
542:.
539::
526:.
523::
510:.
507::
494:.
491::
477:.
474::
457:.
454::
438:.
435::
415:.
412::
399:.
377:.
374::
325:V
321:V
317:V
313:V
309:V
305:V
292:)
284:V
271:V
267:V
251:V
236:V
232:V
228:V
224:V
220:V
216:V
212:V
184:V
50:V
44:V
40:(
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.