STRUCTURE-ACTIVITY ANALYSIS OF A CONUS PEPTIDE BLOCKER OF N-TYPE NEURONAL CALCIUM CHANNELS

The synthetic peptide SNX-111 corresponding to the sequence of the ome ga-conopeptide MVIIA from the venom of the marine snail Conus magus is a highly potent and selective antagonist of N-type calcium channels. We have synthesized and characterized a large number of analogs of SNX -111 in order to elucidate the structural features of the peptide invo lved in blocking N-type calcium channels. Comparison of the binding of SNX-111 and its analogs to rat brain synaptosomal membranes rich in N -type channels revealed that, among the four lysines and two arginines in the molecule, lysine in position 2 and arginines at position 10 an d 21 are important for the interaction of SNX-111 with N-type channels . The importance of the middle segment from residues 9 through 14 for this binding interaction was revealed by substitution of the individua l residues as well as by the construction of hybrid peptides in which the residues 9-12 in SNX-111 and another conopeptide, SNX-183, corresp onding to a peptide SVIB from Coitus striatus, were interchanged. Intr oduction of the sequence SRLM from SNX-111 in place of RKTS in positio n 9-12 in SNX-183 resulted in a 38-fold increase in affinity.