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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

TitleF18, a novel small-molecule nonnucleoside reverse transcriptase inhibitor, inhibits HIV-1 replication using distinct binding motifs as demonstrated by resistance selection and docking analysis
Authors
Issue Date2012
PublisherAmerican Society for Microbiology.
Citation
Antimicrobial Agents and Chemotherapy, 2012, v. 56 n. 1, p. 341-351 How to Cite?
AbstractNonnucleoside 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 Identifierhttp://hdl.handle.net/10722/157666
ISSN
2015 Impact Factor: 4.415
2015 SCImago Journal Rankings: 2.322
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Fund for the Control of Infectious DiseasesRFCID09080772
China's 11th Five-Year Mega Project on the prevention and treatment of AIDS, viral hepatitis and other infectious disease2009ZX09501-012
HKU-UDF
LSK Faculty of Medicine Matching Fund
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 FieldValueLanguage
dc.contributor.authorLu, Xen_US
dc.contributor.authorLiu, Len_US
dc.contributor.authorZhang, Xen_US
dc.contributor.authorLau, TCKen_US
dc.contributor.authorTsui, SKWen_US
dc.contributor.authorKang, Yen_US
dc.contributor.authorZheng, Pen_US
dc.contributor.authorZheng, Ben_US
dc.contributor.authorLiu, Gen_US
dc.contributor.authorChen, Zen_US
dc.date.accessioned2012-08-08T08:52:05Z-
dc.date.available2012-08-08T08:52:05Z-
dc.date.issued2012en_US
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 2012, v. 56 n. 1, p. 341-351en_US
dc.identifier.issn0066-4804en_US
dc.identifier.urihttp://hdl.handle.net/10722/157666-
dc.description.abstractNonnucleoside 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.languageengen_US
dc.publisherAmerican Society for Microbiology.-
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_US
dc.rightsAntimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology.-
dc.subject.meshAnti-HIV agents - chemical synthesis - pharmacology-
dc.subject.meshHIV infections - drug therapy - virology-
dc.subject.meshHIV reverse transcriptase - antagonists and inhibitors - genetics - metabolism-
dc.subject.meshPyranocoumarins - chemical synthesis - pharmacology-
dc.subject.meshReverse transcriptase inhibitors - chemical synthesis - pharmacology-
dc.subject.meshHIV-1 - drug effects - enzymology - genetics-
dc.subject.meshDrug resistance, Viral - drug effects-
dc.subject.meshDrug synergism-
dc.subject.meshGenotype-
dc.subject.meshAmino acid motifs-
dc.subject.meshVirus replication - drug effects-
dc.subject.meshBinding sites-
dc.subject.meshCells, Cultured-
dc.subject.meshLeukocytes, Mononuclear - drug effects - virology-
dc.subject.meshMicrobial sensitivity tests-
dc.subject.meshModels, Molecular-
dc.subject.meshMutation-
dc.subject.meshNevirapine - pharmacology-
dc.titleF18, a novel small-molecule nonnucleoside reverse transcriptase inhibitor, inhibits HIV-1 replication using distinct binding motifs as demonstrated by resistance selection and docking analysisen_US
dc.typeArticleen_US
dc.identifier.emailLiu, L: liuli71@hkucc.hku.hken_US
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hken_US
dc.identifier.emailChen, Z: zchenai@hku.hk-
dc.identifier.authorityLiu, L=rp00268en_US
dc.identifier.authorityZheng, B=rp00353en_US
dc.identifier.authorityChen, Z=rp00243-
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1128/AAC.05537-11en_US
dc.identifier.pmid22037848-
dc.identifier.pmcidPMC3256034-
dc.identifier.scopuseid_2-s2.0-84455161713en_US
dc.identifier.hkuros206301-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84455161713&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume56en_US
dc.identifier.issue1en_US
dc.identifier.spage341en_US
dc.identifier.epage351en_US
dc.identifier.eissn1098-6596-
dc.identifier.isiWOS:000298404900042-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridChen, Z=35271180800en_US
dc.identifier.scopusauthoridLiu, G=36077582900en_US
dc.identifier.scopusauthoridZheng, B=7201780588en_US
dc.identifier.scopusauthoridZheng, P=35764140600en_US
dc.identifier.scopusauthoridKang, Y=54793057300en_US
dc.identifier.scopusauthoridTsui, SKW=7004961364en_US
dc.identifier.scopusauthoridLau, TCK=36981810500en_US
dc.identifier.scopusauthoridZhang, X=54793820200en_US
dc.identifier.scopusauthoridLiu, L=36068379000en_US
dc.identifier.scopusauthoridLu, X=35215493700en_US

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