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F18, a Novel Small-Molecule Nonnucleoside Reverse Transcriptase Inhibitor, Inhibits HIV-1 Replication Using Distinct Binding Motifs as Demonstrated by Resistance Selection and Docking Analysis
- Source :
- Antimicrobial Agents and Chemotherapy. 56:341-351
- Publication Year :
- 2012
- Publisher :
- American Society for Microbiology, 2012.
-
Abstract
- Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components of antiretroviral therapy drug regimen against human immunodeficiency virus type 1 (HIV-1) replication. We previously described a newly synthesized small molecule, 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a (+)-calanolide A analog, as a novel anti-HIV-1 NNRTI (H. Xue et al., J. Med. Chem. 53:1397-1401, 2010). Here, we further investigated its antiviral range, drug resistance profile, and underlying mechanism of action. F18 consistently displayed potent activity against primary HIV-1 isolates, including various subtypes of group M, circulating recombinant form (CRF) 01_AE, and laboratory-adapted drug-resistant viruses. Moreover, F18 displayed distinct profiles against 17 NNRTI-resistant pseudoviruses, with an excellent potency especially against one of the most prevalent strains with the Y181C mutation (50% effective concentration, 1.0 nM), which was in stark contrast to the extensively used NNRTIs nevirapine and efavirenz. Moreover, we induced F18-resistant viruses by in vitro serial passages and found that the mutation L100I appeared to be the dominant contributor to F18 resistance, further suggesting a binding motif different from that of nevirapine and efavirenz. F18 was nonantagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected peripheral blood mononuclear cells. Interestingly, F18 displayed a highly synergistic antiviral effect with nevirapine against nevirapine-resistant virus (Y181C). Furthermore, in silico docking analysis suggested that F18 may bind to the HIV-1 reverse transcriptase differently from other NNRTIs. This study presents F18 as a new potential drug for clinical use and also presents a new mechanism-based design for future NNRTI.<br />link_to_OA_fulltext
- Subjects :
- Models, Molecular
Nevirapine
Efavirenz
Genotype
Anti-HIV Agents
Binding sites
Anti-HIV agents - chemical synthesis - pharmacology
HIV Infections
Drug resistance
Microbial sensitivity tests
Biology
Virus Replication
Antiviral Agents
Pyranocoumarins
Virus
HIV reverse transcriptase - antagonists and inhibitors - genetics - metabolism
chemistry.chemical_compound
Reverse transcriptase inhibitors - chemical synthesis - pharmacology
Drug Resistance, Viral
Amino acid motifs
medicine
Humans
Pharmacology (medical)
Cells, Cultured
Pharmacology
Reverse-transcriptase inhibitor
Nevirapine - pharmacology
Leukocytes, Mononuclear - drug effects - virology
Virus replication - drug effects
Pyranocoumarins - chemical synthesis - pharmacology
virus diseases
HIV infections - drug therapy - virology
Drug resistance, Viral - drug effects
Virology
HIV Reverse Transcriptase
Reverse transcriptase
Infectious Diseases
Mechanism of action
chemistry
Docking (molecular)
Mutation
HIV-1
Leukocytes, Mononuclear
Reverse Transcriptase Inhibitors
HIV-1 - drug effects - enzymology - genetics
Drug synergism
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 10986596 and 00664804
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy
- Accession number :
- edsair.doi.dedup.....af964681c4f6cef0777eeb748e5ae0ef