Abstract
The biologically relevant and active forms of human immunodeficiency viruses type 1 and 2 reverse transcriptase found in infectious virions are heterodimers produced in a two-step dimerization process. Dimerization involves first the rapid association of the two subunits, followed by a slow conformational change yielding a fully active form. We have shown that the dimeric nature of reverse transcriptase represents a important target for the design of a new class of antiviral agents. In this work, we propose a new strategy for its inhibition by targeting protein/protein interactions during viral formation in infected cells. From the screening of peptides derived from the tryptophan cluster at the interface of the connection subdomain, we have designed a short peptide (10 residues) corresponding to residues 395-404, which can block dimerization of reverse transcriptase in vitro and in infected cells. This peptide is highly efficient in abolishing the production of viral particles, without any adverse toxic side effects, when transduced into human immunodeficiency virus type 1-infected cells together with a new peptide carrier.
Highlights
The biologically relevant and active forms of human immunodeficiency viruses type 1 and 2 reverse transcriptase found in infectious virions are heterodimers produced in a two-step dimerization process
We have demonstrated that heterodimeric Reverse transcriptase (RT) are produced in a two-step dimerization process, which involves the rapid association of the two subunits into an inactive dimer, followed by a slow conformational change yielding the fully active form [12, 13]
Based on the x-ray crystallographic structure of HIV-1 RT, we have shown that the first interaction between p66 and p51 occurs in a Trp-rich hydrophobic cluster located in the connection subdomain of the two subunits and is followed by a conformational change that stacks the thumb subdomain of p51 onto the RNase-H domain of p66 and places the fingers subdomain of p51 in the palm subdomain of p66 [12]
Summary
From the screening of peptides derived from the tryptophan cluster at the interface of the connection subdomain, we have designed a short peptide (10 residues) corresponding to residues 395– 404, which can block dimerization of reverse transcriptase in vitro and in infected cells This peptide is highly efficient in abolishing the production of viral particles, without any adverse toxic side effects, when transduced into human immunodeficiency virus type 1-infected cells together with a new peptide carrier. We demonstrate that a short peptide (10 residues) derived from the tryptophan cluster at the interface of the connection subdomains inhibits dimerization of RT in vitro and abolishes the production of viral particles without any adverse toxic side effects when transduced into HIV-1 infected cells
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