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 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.
Morris
M C
MC
Biophysics Department, Centre de Recherches de Biochimie Macromoléculaire, CNRS, 1919 Route de Mende, 34283 Montpellier, Cedex 5, France.
Robert-Hebmann
V
V
Chaloin
L
L
Mery
J
J
Heitz
F
F
Devaux
C
C
Goody
R S
RS
Divita
G
G
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D019281:Dimerization; D015195:Drug Design; D004795:Enzyme Stability / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
D000998:Antiviral Agents; C121378:HIV-1 reverse transcriptase (395-404); D010446:Peptide Fragments; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase