Abstract

The structure of peptide p6.7, a mimotope of the nicotinic receptor ligand site that binds alpha-bungarotoxin and neutralizes its toxicity, was compared to that of the acetylcholine binding protein. The central loop of p6.7, when complexed with alpha-bungarotoxin, fits the structure of the acetylcholine binding protein (AChBP) ligand site, whereas peptide terminal residues seem to be less involved in toxin binding. The minimal binding sequence of p6.7 was confirmed experimentally by synthesis of progressively deleted peptides. Affinity maturation was then achieved by random addition of residues flanking the minimal binding sequence and by selection of new alpha-bungarotoxin binding peptides on the basis of their dissociation kinetic rate. The MAP peptide binds alpha-bungarotoxin in solution and inhibits its binding to the receptor with a K(A) and an IC(50) similar to the monomeric peptide. Peptidomimetics are designed to circumvent some of the problems associated with a natural peptide: e.g. stability against proteolysis (duration of activity) and poor bioavailability. In this regard, we discuss its potential to become a routinely used drug design tool of QM/MM in rational drug discovery and molecular diversity for the construction of anti-alpha-bungarotoxin binding peptide mimetic antidotes consisting of essential elements with high affinity and promised vivo efficiency.

Keywords

QM/MM, rational drug discovery, molecular diversity, construction, anti-alpha-bungarotoxin, binding peptide, mimetic antidotes, elements, high affinity, MAP-p6.7 peptide mimetic ligand, nicotinic receptor, binding site, potent snake neurotoxin, synthetic antidote, merging, scoring, molecular interactions,