ABSTRACT
BACKGROUND: Although major efforts have been devoted to the effective treatment of HIV-1 infection, it has remained one of the leading causes of deaths around the world. So, development of anti-HIV-1 agents featuring novel structure is essential. OBJECTIVE: To synthesize novel quinazolinone derivatives and evaluate their anti-HIV-1 activity. METHOD: In this study, we designed and synthesized a series of novel 2,3-diaryl-4-quinazolinone derivatives using a one-pot multicomponent reaction. Then, the resulting derivatives were evaluated for anti-HIV-1 activity using Hela cell-based single-cycle replication assay. RESULTS: Most of the compounds showed efficacy against HIV-1 replication and the compound 9c exhibited the highest activity with EC50 value of 37 µM. Docking studies indicated that synthesized compounds can interact with the key residues of the HIV-1 integrase active site. Binding of the most active compound was consistent with the HIV-1 integrase inhibitors. CONCLUSION: Based on our results, these derivatives represent novel lead compounds for the development of new promising anti-HIV-1 agents.
Subject(s)
Anti-HIV Agents/chemistry , Chemistry Techniques, Synthetic , Drug Design , Molecular Docking Simulation , Molecular Dynamics Simulation , Quinazolinones/chemistry , Anti-HIV Agents/pharmacology , Cell Survival/drug effects , HIV Infections/virology , HIV-1/drug effects , Humans , Microbial Sensitivity Tests , Molecular Structure , Quinazolinones/pharmacology , Structure-Activity RelationshipABSTRACT
Inactivation of the reverse transcriptase (RT) and integrase (IN) enzymes can abolish the replication of the human immunodeficiency virus (HIV) and, thus, its infectivity. Here, inactivated HIV particles convenient for designing virus-like particle (VLP) based vaccines have been produced. Inactivated HIV-provirus was created by introducing a frame shift mutation. HIV provirus DNA was cut in the pol region by Age I restriction enzyme, followed by filling of sticky ends using the Klenow fragment before ligation. The resulting plasmid was named as pRINNL4-3. HEK-293T cells were used as producer, after being transfected with the modified plasmid. Viral particle production and biological activity were assayed by virus capsid protein (p24) quantification and syncytium formation in MT2 cells, respectively. The immunogenicity of the RINNL4-3 virions was investigated in a mouse model. The mutation was expected to inactivate the virus RT and IN enzymes. The results showed that the VLPs were assembled, as measured by the p24 load of the culture supernatant, and contained functional envelope proteins (Env) as monitored by the syncytium formation. However, these VLPs had no ability to infect target MT2 cells, as well as their VSVG (vesicular stomatitis virus-glycoprotein) pseudotyped counterparts infected HEK-293T cells. A high level of antibody response was observed in immunized mice. Since RINNL4-3 virions are replication incompetent, they are convenient for production and use in biomedical studies. Also, RINNL4-3 is a candidate for a vaccine development due to it contains envelope and structural virus proteins which are crucial for triggering neutralizing antibodies and the cellular immune response.
