Abstract
Reverse transcriptases from both human immunodeficiency viruses type 1 and 2 are obligatory dimers. A tryptophan-rich repeat motif that is highly conserved between these proteins, as well as in the reverse transcriptase from simian immunodeficiency virus, has been postulated to be involved in hydrophobic subunit interactions. A synthetic 19-mer peptide covering part of this tryptophan repeat motif was recently shown to inhibit human immunodeficiency viruses type 1 reverse transcriptase subunit dimerization (Divita, G., Restle, T., Goody, R. S., Chermann, J.-C., and Baillon, J. G. (1994) J. Biol. Chem. 269, 13080-13083). In the present study, we show that the same peptide can also inhibit human immunodeficiency virus type 2 reverse transcriptase subunit dimerization, suggesting that the same inhibitors might be used as agents against both viruses as well as against variants of human immunodeficiency virus type 1 that differ from the variant against which they were developed. Under appropriate experimental conditions, e.g. at acidic pH, this peptide is also able to induce the dissociation of the enzyme from human immunodeficiency virus type 1.
Highlights
A significant effort has been made over the past few years toward improving or finding new and more potent and specific inhibitors of reverse transcriptase (RT)1 of human immunodeficiency virus (HIV), the etiologic agent responsible for the development of AIDS
Peptides Derived from the Connection Domain of HIV-1 RT as Inhibitors of HIV-2 RT Dimerization—We have recently proposed that the formation of the native heterodimeric form of both HIV-1 and HIV-2 RTs occurs in a two-step process, the first corresponding to the association of the two subunits to give an inactive intermediate, which slowly isomerizes to the “mature” RT (Divita et al, 1995)
Heterodimeric HIV-1 and HIV-2 RTs represent the biologically active relevant forms found in infectious virions (Chandra et al, 1986; Di-Marzo Veronese et al, 1986; Lightfoote et al, 1986; DeVico et al, 1989), and their dimeric nature presents an interesting target for the design of new antiviral agents (Restle et al, 1990; Divita et al, 1994)
Summary
A significant effort has been made over the past few years toward improving or finding new and more potent and specific inhibitors of reverse transcriptase (RT)1 of human immunodeficiency virus (HIV), the etiologic agent responsible for the development of AIDS. A synthetic 19-mer peptide covering part of this tryptophan repeat motif was recently shown to inhibit human immunodeficiency viruses type 1 reverse transcriptase subunit dimerization
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