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- Publisher Website: 10.1128/AAC.05537-11
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Article: 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
Title | 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 | ||||||||||
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Authors | |||||||||||
Issue Date | 2012 | ||||||||||
Publisher | American Society for Microbiology. | ||||||||||
Citation | Antimicrobial Agents and Chemotherapy, 2012, v. 56 n. 1, p. 341-351 How to Cite? | ||||||||||
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. | ||||||||||
Persistent Identifier | http://hdl.handle.net/10722/157666 | ||||||||||
ISSN | 2023 Impact Factor: 4.1 2023 SCImago Journal Rankings: 1.357 | ||||||||||
PubMed Central ID | |||||||||||
ISI Accession Number ID |
Funding Information: This work was supported by Hong Kong Research Fund for the Control of Infectious Diseases (RFCID09080772 to ZC) and the China's 11th Five-Year Mega Project on the prevention and treatment of AIDS, viral hepatitis and other infectious disease (2009ZX09501-012 to GL). We also thank the HKU-UDF and LSK Faculty of Medicine Matching Fund for financial supports to HKU AIDS Institute. | ||||||||||
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lu, X | en_US |
dc.contributor.author | Liu, L | en_US |
dc.contributor.author | Zhang, X | en_US |
dc.contributor.author | Lau, TCK | en_US |
dc.contributor.author | Tsui, SKW | en_US |
dc.contributor.author | Kang, Y | en_US |
dc.contributor.author | Zheng, P | en_US |
dc.contributor.author | Zheng, B | en_US |
dc.contributor.author | Liu, G | en_US |
dc.contributor.author | Chen, Z | en_US |
dc.date.accessioned | 2012-08-08T08:52:05Z | - |
dc.date.available | 2012-08-08T08:52:05Z | - |
dc.date.issued | 2012 | en_US |
dc.identifier.citation | Antimicrobial Agents and Chemotherapy, 2012, v. 56 n. 1, p. 341-351 | en_US |
dc.identifier.issn | 0066-4804 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/157666 | - |
dc.description.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. | en_US |
dc.language | eng | en_US |
dc.publisher | American Society for Microbiology. | - |
dc.relation.ispartof | Antimicrobial Agents and Chemotherapy | en_US |
dc.rights | Antimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology. | - |
dc.subject.mesh | Anti-HIV agents - chemical synthesis - pharmacology | - |
dc.subject.mesh | HIV infections - drug therapy - virology | - |
dc.subject.mesh | HIV reverse transcriptase - antagonists and inhibitors - genetics - metabolism | - |
dc.subject.mesh | Pyranocoumarins - chemical synthesis - pharmacology | - |
dc.subject.mesh | Reverse transcriptase inhibitors - chemical synthesis - pharmacology | - |
dc.subject.mesh | HIV-1 - drug effects - enzymology - genetics | - |
dc.subject.mesh | Drug resistance, Viral - drug effects | - |
dc.subject.mesh | Drug synergism | - |
dc.subject.mesh | Genotype | - |
dc.subject.mesh | Amino acid motifs | - |
dc.subject.mesh | Virus replication - drug effects | - |
dc.subject.mesh | Binding sites | - |
dc.subject.mesh | Cells, Cultured | - |
dc.subject.mesh | Leukocytes, Mononuclear - drug effects - virology | - |
dc.subject.mesh | Microbial sensitivity tests | - |
dc.subject.mesh | Models, Molecular | - |
dc.subject.mesh | Mutation | - |
dc.subject.mesh | Nevirapine - pharmacology | - |
dc.title | 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 | en_US |
dc.type | Article | en_US |
dc.identifier.email | Liu, L: liuli71@hkucc.hku.hk | en_US |
dc.identifier.email | Zheng, B: bzheng@hkucc.hku.hk | en_US |
dc.identifier.email | Chen, Z: zchenai@hku.hk | - |
dc.identifier.authority | Liu, L=rp00268 | en_US |
dc.identifier.authority | Zheng, B=rp00353 | en_US |
dc.identifier.authority | Chen, Z=rp00243 | - |
dc.description.nature | link_to_OA_fulltext | en_US |
dc.identifier.doi | 10.1128/AAC.05537-11 | en_US |
dc.identifier.pmid | 22037848 | - |
dc.identifier.pmcid | PMC3256034 | - |
dc.identifier.scopus | eid_2-s2.0-84455161713 | en_US |
dc.identifier.hkuros | 206301 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-84455161713&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 56 | en_US |
dc.identifier.issue | 1 | en_US |
dc.identifier.spage | 341 | en_US |
dc.identifier.epage | 351 | en_US |
dc.identifier.eissn | 1098-6596 | - |
dc.identifier.isi | WOS:000298404900042 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Chen, Z=35271180800 | en_US |
dc.identifier.scopusauthorid | Liu, G=36077582900 | en_US |
dc.identifier.scopusauthorid | Zheng, B=7201780588 | en_US |
dc.identifier.scopusauthorid | Zheng, P=35764140600 | en_US |
dc.identifier.scopusauthorid | Kang, Y=54793057300 | en_US |
dc.identifier.scopusauthorid | Tsui, SKW=7004961364 | en_US |
dc.identifier.scopusauthorid | Lau, TCK=36981810500 | en_US |
dc.identifier.scopusauthorid | Zhang, X=54793820200 | en_US |
dc.identifier.scopusauthorid | Liu, L=36068379000 | en_US |
dc.identifier.scopusauthorid | Lu, X=35215493700 | en_US |
dc.identifier.issnl | 0066-4804 | - |