Synthesis Of HIV-1 Vif Inhibitors And Evaluation Of Their In Vitro Activity

Since the first case of AIDS was found in the late 80s,the disease has spread all over the world quickly,and has become a big problem for the whole world.Even today there is no method that can thoroughly cure AIDS.At present the most effective way to cure AIDS is Highly Active Anti-Retroviral Therapy(HAART).However,due to the drug resistance and the side effects of the drugs,the HAART does not perform very well.Therefore,looking for new therapeutic targets and synthesis of new antiviral drugs is the top priority.Viral infectivity factor(Vif),a helper protein of HIV-1,can safeguard the virus replication in the infected cells.Vif recruits cellular Elongin B/C-Cullin5 E3 ubiquitin ligase to target the host antiviral protein APOBEC3G(A3G)for proteasomal degradation.In the absence of Vif,A3G is packaged into budding HIV-1 virions and introduces multiple mutations in the newly synthesized minus-strand viral cDNA to restrict virus replication.Thus,the A3G-Vif-E3 complex represents an attractive target for development of novel anti-HIV drugs.In the second chapter of this paper,we modified the compound RN-19 which has been reported before,and synthesized 30 compounds.Characterization by 1H NMR,13C NMR,MS and HPLC methods proved these compounds to be synthesized successfully.In the third chapter of this paper,the antiviral activity of the synthetic compounds was tested.Using MTT method to detect the cytotoxicity of these compounds on cells(A549),we confirmed that the toxicity of compounds complies with the standard of drug tests.Then we co-transfected A3G-GFP and Vif in the 293T cells,and evaluated the change of the fluorescence intensity of green fluorescent protein after adding compounds to indirectly assess the antiviral ability of compounds.Through repeated screening,we picked out the best inhibitor(PDZJ-DBr)from all the RN-19 derivatives that we synthesized.