SOLUTION STRUCTURE OF RP-71955, A NEW 21 AMINO-ACID TRICYCLIC PEPTIDEACTIVE AGAINST HIV-1 VIRUS

The structure of RP 71955, a new tricyclic 21 amino acid peptide activ e against human immunodeficiency virus 1, was determined. Its amino ac id composition was inferred from the results of fast atom bombardment mass spectrometry, nuclear magnetic resonance, Raman spectroscopy, and amino acid analysis. Its sequence could not be determined classically , using Edman degradation, given the lack of a free terminal NH2. It w as deduced from the interpretation of interresidue nuclear Overhauser effects and confirmed by the sequencing of peptides obtained by limite d chemical hydrolysis. It was found to be CLGIGSCNDFAGCGYAVVCFW. An in ternal amide bond between the NH2 of C1 and the gamma-COOH of D9 was o bserved, as well as two disulfide bridges, one between C1 and C13 and one between C7 and C19. The three-dimensional structure of RP 71955 wa s determined from nuclear magnetic resonance derived constraints using distance geometry, restrained molecular dynamics, nuclear Overhauser effect back calculation, and an iterative refinement using a full rela xation matrix approach. Analogies between the structure of RP 71955 an d some functional domains of gp41, the transmembrane protein of human immunodeficiency virus 1, suggest hypotheses concerning the mode of ac tion of RP 71955.