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Titolo:
Design and synthesis of peptides that bind alpha-bungarotoxin with high affinity
Autore:
Kasher, R; Balass, M; Scherf, T; Fridkin, M; Fuchs, S; Katchalski-Katzir, E;
Indirizzi:
Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel Weizmann Inst Sci Rehovot Israel IL-76100 Chem, IL-76100 Rehovot, Israel Weizmann Inst Sci, Dept Chem Serv, IL-76100 Rehovot, Israel Weizmann Inst Sci Rehovot Israel IL-76100 Serv, IL-76100 Rehovot, Israel Weizmann Inst Sci, Dept Organ Chem, IL-76100 Rehovot, Israel Weizmann InstSci Rehovot Israel IL-76100 Chem, IL-76100 Rehovot, Israel Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel Weizmann Inst Sci Rehovot Israel IL-76100 unol, IL-76100 Rehovot, Israel
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 2, volume: 8, anno: 2001,
pagine: 147 - 155
SICI:
1074-5521(200102)8:2<147:DASOPT>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
NICOTINIC ACETYLCHOLINE-RECEPTOR; TORPEDO-CALIFORNICA; SITE; SUBUNIT; LIBRARY; DOMAIN; SNAKE;
Keywords:
alpha-bungarotoxin; acetylcholine receptor; systematic residue replacement;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
15
Recensione:
Indirizzi per estratti:
Indirizzo: Katchalski-Katzir, E Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel Weizmann Inst Sci Rehovot Israel IL-76100 t, Israel
Citazione:
R. Kasher et al., "Design and synthesis of peptides that bind alpha-bungarotoxin with high affinity", CHEM BIOL, 8(2), 2001, pp. 147-155

Abstract

Background: alpha -Bungarotoxin (alpha -BTX) is a highly toxic snake venomalpha -neurotoxin that binds to acetylcholine receptor (AChR) at the neuromuscular junction, and is a potent inhibitor of this receptor. We describe the design and synthesis of peptides that bind alpha -BTX with high affinity, and inhibit its interaction with AChR with an IC50 of 2 nM. The design of these peptides was based on a lead peptide with an IC50 Of 3 x 10(-7) M, previously identified by us [M. Balass et al., Proc. Natl. Acad. Sci. USA 94 (1997) 6054] using a phage-display peptide library. Results: Employing nuclear magnetic resonance-derived structural information [T. Scherf et al., Proc. Natl. Acad. Sci. USA 94 (1997) 6059] of the complex of (alpha -BTX with the lead peptide, as well as structure-function analysis of the ligand-binding site of AChR, a systematic residue replacementof the lead peptide, one position at a time, yielded 45 different 13-mer peptides. Of these, two peptides exhibited a one order of magnitude increasein inhibitory potency in comparison to the lead peptide. The design of additional peptides, with two or three replacements, resulted in peptides thatexhibited a further increase in inhibitory potency (IC50 values of 2 nM), that is more than two orders of magnitude better than that of the original lead peptide, and better than that of any known peptide derived from AChR sequence. The high affinity peptides had a protective effect on mice against(alpha -BTX lethality. Conclusions: Synthetic peptides with high affinity to (alpha -BTX may be used as potential lead compounds for developing effective antidotes against alpha -BTX poisoning. Moreover, the procedure employed in this study may serve as a general approach for the design and synthesis of peptides that interact with high affinity with any desired biological target. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 19:38:08