- 作者: Laurent Chaloin; Fatima Smagulova; Elana Hariton-Gazal; Laurence Briant; Abraham Loyter; Christian Devaux
- 作者服務機構: 1 Centre detudes dagents Pathogenes et Biotechnologies pour la Sante (CPBS), Institut de Biologie, CNRS UMR5236-UM1-UM2, 4 BoulevardHenri IV, CS69033, 34965, Montpellier cedex 2, France; ; 2 Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 99104, Jerusalem, Israel
- 中文摘要: --
- 英文摘要: 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 Pr55gag and gp160env 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.
- 中文關鍵字: --
- 英文關鍵字: antiviral peptides, arginine rich motif, backbone cyclic peptide, HIV, Rev