ABSTRACT
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S)-3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 µmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs.
Subject(s)
Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Lignans/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemical synthesis , Drug Discovery , Lignans/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesisABSTRACT
Phytochemical investigation on the whole plant of Chloranthus japonicus (Chloranthaceae) led to the isolation and identification of three new lindenane-type sesquiterpenoid dimers, chlorajaponilides F-H (1-3), along with seven known ones (4-10). Their chemical structures were established by extensive spectral evidence. Compounds 1 and 2 are both dimeric sesquiterpenoids featuring a rare hydroperoxy group at C-5. All compounds were tested for their activities on wild type HIV-1 replication and compounds 1, 2, 5, and 9 were effective with EC50 values from 3.08 to 17.16µM. All these four compounds showed the same inhibitory effects on the two NNRTI-resistant HIV strains as on wild-type HIV-1 with EC50 change folds from 0.61 to 1.6µM. Furthermore, compounds 1, 5, and 9 exhibited inhibitory activities on HCV replication with the similar potency as their activities on HIV-1. Our finding may provide a clue to address the problem of HIV-1 and HCV co-infection.
Subject(s)
Antiviral Agents/chemistry , HIV-1/drug effects , Hepacivirus/drug effects , Magnoliopsida/chemistry , Sesquiterpenes/chemistry , Virus Replication/drug effects , Antiviral Agents/isolation & purification , HEK293 Cells , HIV-1/physiology , Hepacivirus/physiology , Humans , Molecular Structure , Sesquiterpenes/isolation & purificationABSTRACT
This study is to evaluate the HAART pharmacodynamics with dolutegravir as the "anchor" in vitro. A nucleoside reverse transcriptase inhibitors (NRTIs) resistant recombinant virus model (VSVG/HIV-1(RT-D67N,K70R,T215F)) and an integrase inhibitors (INIs) resistant recombinant virus model (VSVG/HIV-1(IN-G140S,QI48H)) were constructed and established. The anti-viral pharmacodynamics was evaluated with drug combinations including two NRTIs along with one INI or one NNRTI. The results showed that the combination with an INI gave a stronger synergism on wild type HIV-1 replication comparing to that with an NNRTI. Comparing the two INIs as the "anchor" for HAART, DTG exhibited an equivalent CI to that of RAL on wild type HIV-1 replication; but a greater synergy than RAL on INI-resistant HIV-1 replication. Besides of the pharmacodynamics results of DTG-based drug combination, the results may contribute to clinical antiviral therapy.
