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postgraduate thesis: Mechanism study of a small molecule F18 as a novel anti-HIV-1 non-nucleoside reverse transcriptase inhibitor
Title | Mechanism study of a small molecule F18 as a novel anti-HIV-1 non-nucleoside reverse transcriptase inhibitor |
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Authors | |
Advisors | |
Issue Date | 2012 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Lu, X. [陆小凡]. (2012). Mechanism study of a small molecule F18 as a novel anti-HIV-1 non-nucleoside reverse transcriptase inhibitor. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4724650 |
Abstract | Non-nucleoside reverse transcriptase inhibitor (NNRTI) is one of the key components of antiretroviral drug regimen against human immunodeficiency virus type-1 (HIV-1) replication. However, the low genetic barriers to drug-resistance or cross-resistance, side effects, as well as the unaffordable cost of NNRTIs compromise their clinical usage. Therefore, to develop novel NNRTIs with potent antiviral activity against HIV-1 becomes a major concern in the treatment and prevention of HIV/AIDS.
(+)-Calanolide A, which is a natural product initially extracted from the tropical rainforest tree Calophyllum lanigerum, was identified as an attractive NNRTI against HIV-1 despite virus strains containing drug-resistant K103N/Y181C mutations. In this study, a chemical library was constructed based on the three chiral carbon centers of (+)-Calanolide A. After screening the activity against HIVNL4-3 wild-type and several NNRTI-resistant pseudoviruses, a small molecule 10-chloromethyl-11- demethyl-12-oxo-calanolide A (F18) was identified as novel NNRTI with promising anti-HIV efficacy.
Further studies were performed to investigate the antiviral breadth, drug resistance profile and underlying mechanism of the action of F18. F18 consistently displayed a potent activity against primary HIV-1 isolates including various subtypes of M group, CRF01_AE, and laboratory-adapted drug-resistant viruses in PBMC based assay. 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 (EC50=1.0nM) in cell line based assay, which was in stark contrast from the extensively used NNRTIs nevirapine and efavirenz. F18-resistant viruses were induced by in vitro serial passages, and mutation L100I was appeared to be the dominant contributor to F18-resistance, further suggesting a binding motif different from nevirapine and efavirenz. The efficacy of F18 was non-antagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected PBMCs. 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 in a way different to other NNRTIs. For the potential as an anti-HIV-1 microbicide, F18 also showed the stable and rapid release, as well as the sustained antiviral activity against HIV-1 wild-type virus in a formulation temperature-sensitive acidic gel.
In summary, this study presents F18 as a new potential drug for clinical use and also underlies new mechanism-based design for future NNRTI. |
Degree | Doctor of Philosophy |
Subject | AIDS (Disease) - Chemotherapy. HIV infections - Chemotherapy. Reverse transcriptase - Inhibitors - Therapeutic use. Antiretroviral agents. |
Dept/Program | Microbiology |
Persistent Identifier | http://hdl.handle.net/10722/146137 |
HKU Library Item ID | b4724650 |
DC Field | Value | Language |
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dc.contributor.advisor | Chen, Z | - |
dc.contributor.advisor | Zheng, B | - |
dc.contributor.author | Lu, Xiaofan. | - |
dc.contributor.author | 陆小凡. | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | Lu, X. [陆小凡]. (2012). Mechanism study of a small molecule F18 as a novel anti-HIV-1 non-nucleoside reverse transcriptase inhibitor. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4724650 | - |
dc.identifier.uri | http://hdl.handle.net/10722/146137 | - |
dc.description.abstract | Non-nucleoside reverse transcriptase inhibitor (NNRTI) is one of the key components of antiretroviral drug regimen against human immunodeficiency virus type-1 (HIV-1) replication. However, the low genetic barriers to drug-resistance or cross-resistance, side effects, as well as the unaffordable cost of NNRTIs compromise their clinical usage. Therefore, to develop novel NNRTIs with potent antiviral activity against HIV-1 becomes a major concern in the treatment and prevention of HIV/AIDS. (+)-Calanolide A, which is a natural product initially extracted from the tropical rainforest tree Calophyllum lanigerum, was identified as an attractive NNRTI against HIV-1 despite virus strains containing drug-resistant K103N/Y181C mutations. In this study, a chemical library was constructed based on the three chiral carbon centers of (+)-Calanolide A. After screening the activity against HIVNL4-3 wild-type and several NNRTI-resistant pseudoviruses, a small molecule 10-chloromethyl-11- demethyl-12-oxo-calanolide A (F18) was identified as novel NNRTI with promising anti-HIV efficacy. Further studies were performed to investigate the antiviral breadth, drug resistance profile and underlying mechanism of the action of F18. F18 consistently displayed a potent activity against primary HIV-1 isolates including various subtypes of M group, CRF01_AE, and laboratory-adapted drug-resistant viruses in PBMC based assay. 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 (EC50=1.0nM) in cell line based assay, which was in stark contrast from the extensively used NNRTIs nevirapine and efavirenz. F18-resistant viruses were induced by in vitro serial passages, and mutation L100I was appeared to be the dominant contributor to F18-resistance, further suggesting a binding motif different from nevirapine and efavirenz. The efficacy of F18 was non-antagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected PBMCs. 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 in a way different to other NNRTIs. For the potential as an anti-HIV-1 microbicide, F18 also showed the stable and rapid release, as well as the sustained antiviral activity against HIV-1 wild-type virus in a formulation temperature-sensitive acidic gel. In summary, this study presents F18 as a new potential drug for clinical use and also underlies new mechanism-based design for future NNRTI. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.source.uri | http://hub.hku.hk/bib/B47246509 | - |
dc.subject.lcsh | AIDS (Disease) - Chemotherapy. | - |
dc.subject.lcsh | HIV infections - Chemotherapy. | - |
dc.subject.lcsh | Reverse transcriptase - Inhibitors - Therapeutic use. | - |
dc.subject.lcsh | Antiretroviral agents. | - |
dc.title | Mechanism study of a small molecule F18 as a novel anti-HIV-1 non-nucleoside reverse transcriptase inhibitor | - |
dc.type | PG_Thesis | - |
dc.identifier.hkul | b4724650 | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Microbiology | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_b4724650 | - |
dc.date.hkucongregation | 2012 | - |
dc.identifier.mmsid | 991033026379703414 | - |