RESUMO
During the HIV-1 replication process, interactions between the RNA sequence, named TAR RNA, and the viral protein, Tat, permit a fast and efficient transcription of viral DNA into RNA. Based on the NMR structure of TAR RNA from the PDB, two Peptidic Nucleic Analog- (PNA) based molecules were designed by molecular modelling, the first one targeting G32 U31 and the second targeting U31 C30 free loop bases. Before designing the molecules, the flexibility of the TAR RNA was evaluated by molecular dynamics (MD). The molecules studied are composed of three domains: an arginine, a linker, and two PNA bases. First, molecules were designed and the linker length was optimized to fit the TAR RNA; second, a MD simulation on the TAR RNA molecule complex was performed to validate the molecular structure. Optimal molecules were synthesized and tested on infected cells. The experimental results support the choices made in the design of the molecules.
Assuntos
Simulação por Computador , Produtos do Gene tat/química , Repetição Terminal Longa de HIV , HIV-1/genética , Modelos Moleculares , Conformação de Ácido Nucleico , Ácidos Nucleicos Peptídicos/química , RNA Viral/química , Dicroísmo Circular , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular/métodos , Nylons/química , RNA Viral/antagonistas & inibidores , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
A new family of molecules potentially inhibitors of the HIV-1 Tat-TAR complex was prepared. These compounds are constituted by dinucleotide analogs (PNA dimer) bound, through a linker, to an arginine residue. In this series, several molecules inhibit viral development in cell culture with a micromolar IC50 and without cellular toxicity until 200 microM concentration.
