Potent inhibition of HIV-1 replication by backbone cyclic peptides bearing the Rev arginine rich motif.
Due to its essential role in the virus life cycle, the viral regulatory protein Rev constitutes an attractive target for the development of new antiviral molecules. In this work, a series of Backbone Cyclic Peptide (BCP) analogs that bear a conformationally constrained arginine rich motif (ARM) of Rev were tested for in vitro inhibition of HIV-1 replication. We observed a potent suppression of HIV-1 replication in chronically infected T lymphocytic cells treated with Rev-BCPs. We further investigated possible mechanisms of HIV-1 inhibition and showed that Rev-BCPs interfere slightly with the nuclear import process and are very efficient in blocking a mechanism that controls Pr55(gag) and gp160(env) synthesis. Interestingly, these protein precursors are known to be encoded by mRNAs that require Rev-binding for nuclear export. In situ hybridization using a Cy-3 conjugated HIV-1 gag oligonucleotide probe indicated that Rev-BCPs prevent the intracellular accumulation of unspliced viral RNA. As a model, the most promising analog, Rev-BCP 14, was studied by molecular modeling and dynamics in order to identify its binding site on the Rev Response Element (RRE). The annealing simulation suggests that upon binding on the RRE, Rev-BCP 14 widens the distorted major groove of the viral RNA. Numerous contacts between peptide and RNA were found within the complex and some were identified as key components for the interactions. Altogether, our data indicate that the use of conformationally constrained Rev-BCPs represents a promising strategy for the development of new peptide-based therapeutic agents against HIV-1.
Chaloin
Laurent
L
Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), Institut de Biologie, CNRS UMR5236-UM1-UM2, 4 Boulevard Henri IV, CS69033, 34965, Montpellier cedex 2, France. laurent.chaloin@univ-montp1.fr
Smagulova
Fatima
F
Hariton-Gazal
Elana
E
Briant
Laurence
L
Loyter
Abraham
A
Devaux
Christian
C
D020816:Amino Acid Motifs; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry; D015694:Gene Products, rev / Q000737:chemistry* / Q000235:genetics; D019302:HIV Envelope Protein gp160 / Q000037:antagonists & inhibitors; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011498:Protein Precursors / Q000037:antagonists & inhibitors; D012367:RNA, Viral / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors
D019380:Anti-HIV Agents; D015694:Gene Products, rev; D019302:HIV Envelope Protein gp160; D010456:Peptides, Cyclic; D011498:Protein Precursors; D012367:RNA, Viral; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D001120:Arginine