Efforts are focused on design, synthesis and evaluation of peptides that are expected to act as inhibitors of key biochemical processes in cell proliferation and in retroviral invasion. In Subproject 1, de novo designed peptides were developed that are expected to bind to the specific fusogenic region of the HIV1 envelope glycoprotein gp41, in attempts to inhibit the viral infection of target cells. Design strategy makes use of the 'sense/anti-sense' concept of molecular recognition phenomenon. Peptides were generated based on the noncoding gene sequence, by hydropathic optimization of complementarity, and by optimizing the amino acid pairing interactions. Eight 15-amino acid peptides have been synthesized and characterized to date. Their effectiveness will be tested in assays of inhibiting syncytium formation. Subproject 2 is aimed at developing peptidic agents that inhibit the biochemical signal transduction cascade initiated by autophosphorylation of yrosine kinase proteins. A series of 29 linear and cyclic, hexameric, L- and D-amino acid-containing peptides have been synthesized. A number of these have been found to be inhibitory to the interaction of platelet derived growth factor (PDGF) receptor with the SH2 domain of the p85 subunit of phosphoinositol 3-kinase.
