A new potent HIV-1 reverse transcriptase inhibitor - A synthetic peptide derived from the interface subunit domains

The biologically relevant and active forms of human immunodeficiency viruse s type 1 and 2 reverse transcriptase found in infectious virions are hetero dimers produced in a two-step dimerization process. Dimerization involves f irst the rapid association of the two subunits, followed by a slow conforma tional change yielding a fully active form. We have shown that the dimeric nature of reverse transcriptase represents a important target for the desig n of a new class of antiviral agents. In this work, we propose a new strate gy for its inhibition by targeting protein/protein interactions during vira l formation in infected cells. From the screening of peptides derived from the tryptophan cluster at the interface of the connection subdomain, we hav e designed a short peptide (10 residues) corresponding to residues 395-404, which can block dimerization of reverse transcriptase in vitro and in infe cted cells. This peptide is highly efficient in abolishing the production o f viral particles, without any adverse toxic side effects, when transduced into human immunodeficiency virus type 1-infected cells together with a new peptide carrier.