Design and synthesis of N1-aryl-benzimidazoles 2-substituted as novel HIV-1 non-nucleoside reverse transcriptase inhibitors

A series of novel N₁-aryl-2-arylthioacetamido-benzimidazoles were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Some of them proved to be effective in inhibiting HIV-1 replication at submicromolar and nanomolar concentration acting as HIV-1 non-nucleoside RT inhibitors (NNRTIs), with low cytotoxicity. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed and rationalized by docking studies.     

Towards new C6-rigid S-DABO HIV-1 reverse transcriptase inhibitors: Synthesis,biological investigation and molecular modeling studies

A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N + Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC₅₀ value of 0.26 μM and a selectivity index (SI) of 541. The preliminary structure–activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed.     

Conformational Changes in HIV-1 Reverse Transcriptase that Facilitate Its Maturation

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Error-prone bypass of O6-methylguanine by DNA polymerase of Pseudomonas aeruginosa phage PaP1

O⁶-Methylguanine (O⁶-MeG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, generally leads to G:C to A:T mutagenesis. To study DNA replication encountering O⁶-MeG by the DNA polymerase (gp90) of P. aeruginosa phage PaP1, we analyzed steady-state and pre-steady-state kinetics of nucleotide incorporation opposite O⁶-MeG by gp90 exo⁻. O⁶-MeG partially inhibited full-length extension by gp90 exo⁻. O⁶-MeG greatly reduces dNTP incorporation efficiency, resulting in 67-fold preferential error-prone incorporation of dTTP than dCTP. Gp90 exo⁻ extends beyond T:O⁶-MeG 2-fold more efficiently than C:O⁶-MeG. Incorporation of dCTP opposite G and incorporation of dCTP or dTTP opposite O⁶-MeG show fast burst phases. The pre-steady-state incorporation efficiency (k_pol/K_d,dNTP) is decreased in the order of dCTP:G > dTTP:O⁶-MeG > dCTP:O⁶-MeG. The presence of O⁶-MeG at template does not affect the binding affinity of polymerase to DNA but it weakened their binding in the presence of dCTP and Mg²⁺. Misincorporation of dTTP opposite O⁶-MeG further weakens the binding affinity of polymerase to DNA. The priority of dTTP incorporation opposite O⁶-MeG is originated from the fact that dTTP can induce a faster conformational change step and a faster chemical step than dCTP. This study reveals that gp90 bypasses O⁶-MeG in an error-prone manner and provides further understanding in DNA replication encountering mutagenic alkylation DNA damage for P. aeruginosa phage PaP1.