New Non-Nuceleotide Reverse Transcriptase Inhibitors for Drug Resistant HIV Strains
用于耐药 HIV 菌株的新型非核苷酸逆转录酶抑制剂
基本信息
- 批准号:10337386
- 负责人:
- 金额:$ 52.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-16 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAffinityAmino AcidsAnti-Retroviral AgentsAntiviral AgentsBindingBiological AssayBiological TestingChemicalsClinical Drug DevelopmentClinical TreatmentComputer AssistedComputer ModelsCoupledCrystallizationDockingDrug DesignDrug KineticsDrug TargetingDrug resistanceEffectivenessFutureGoalsHIVHIV drug resistanceHIV resistanceHIV-1HIV-1 drug resistanceHandIn VitroInfectionLigandsMethodologyModernizationModificationMulti-Drug ResistanceMutateMutationNNRTI-resistanceOutcomePatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacology StudyPlayPositioning AttributePreclinical Drug DevelopmentPropertyResearchResistanceResistance developmentResistance profileReverse Transcriptase InhibitorsRoleStructureSystemTechniquesTestingVariantViralVirusWorkantiretroviral therapybasechemical synthesisdesigndrug candidatedrug developmentdrug discoverydrug resistant virusdrug structurefitnessimprovedindexinglead optimizationmeetingsmolecular modelingmouse modelmutantnon-nucleoside reverse transcriptase inhibitorsresistance mutationscreeningsuccess
项目摘要
Abstract
Antiretroviral therapy (ART) for HIV/AIDS is effective in the clinical treatment of HIV-1 infections. Non-nucleoside
reverse transcriptase inhibitors (NNRTIs) are a class of anti-retrovirals playing a major role in the success of
ART. However, the emergence of drug resistant viruses has limited the usefulness of the NNRTIs in many
patients. Thus, new NNRTIs are needed to overcome current NNRTI resistant HIV strains. The goal of this study
is to identify new NNRTIs effective for drug resistant viruses. We have previously discovered two classes of
NNRTIs, diarylanilines (DAANs) and diarylpyridinamines (DAPAs), which are structurally different from the
approved diarylpyrimidine (DAPY)-type drugs etravirine and rilpivirine. Each of the chemical classes can fully
overcome some prevalent NNRTI resistant mutations. However, none of them was effective for all the prevalent
NNRTI resistant HIV-1 variants. To fully overcome the NNRTI resistance, we have identified the key structural
features from each of the chemical classes that are required for effectiveness against drug resistant viruses. We
hypothesize that a compound with structural features effective for drug resistant viruses can be synthesized and
will be effective for viruses resistant to current NNRTIs. To test our hypothesis and to accomplish our goal, we
propose to carry out the following two Specific Aims. Aim 1 is to design and synthesize new diarylaniline (DAAN)
and diarylpyridinamine (DAPA) derivatives to overcome HIV-1 variants resistant to NNRTIs. This aim will be
achieved by designing new NNRTIs that include favorable structural features for overcoming drug resistance
selected from DAANs/DAPAs. Aim 2 is to establish the pharmacological profiles of the new NNRTIs effective
against drug resistant HIV-1. The pharmacological study is aimed at establishing basic/initial pharmacological
profiles to pave the way for future more comprehensive drug-target interaction studies and clinical drug
development. Achieving this aim will provide the essential information to advance the compounds for further
preclinical drug development to mitigate NNRTI resistance. Our chemical synthesis will be supported by
conventional medicinal chemistry and modern molecular modeling. The lead optimization will be guided by well-
established primary and secondary biological testing against wild-type and NNRTI resistant virus, respectively.
The research team is positioned uniquely to conduct this endeavor based on over two decades of anti-HIV
research. With confirmed promising leads already on-hand, coupled with the availability of established bioassay
systems, we feel confident that we can discover and develop new NNRTIs to overcome the prevalent NNRTI
resistant viruses.
摘要
项目成果
期刊论文数量(0)
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Chin-Ho Chen其他文献
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{{ truncateString('Chin-Ho Chen', 18)}}的其他基金
New Non-Nuceleotide Reverse Transcriptase Inhibitors for Drug Resistant HIV Strains
用于耐药 HIV 菌株的新型非核苷酸逆转录酶抑制剂
- 批准号:
10653999 - 财政年份:2021
- 资助金额:
$ 52.44万 - 项目类别:
New Non-Nuceleotide Reverse Transcriptase Inhibitors for Drug Resistant HIV Strains
用于耐药 HIV 菌株的新型非核苷酸逆转录酶抑制剂
- 批准号:
10452754 - 财政年份:2021
- 资助金额:
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Aloperine derivatives as novel anti-influenza agents
作为新型抗流感药物的阿哌林衍生物
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9891004 - 财政年份:2019
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$ 52.44万 - 项目类别:
Small Molecule HIV-1 Entry Inhibitor with Novel Mechanisms of Action
具有新颖作用机制的小分子 HIV-1 进入抑制剂
- 批准号:
9884724 - 财政年份:2018
- 资助金额:
$ 52.44万 - 项目类别:
Quinolizidines as Novel HIV-1 Entry Inhibitors
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9322052 - 财政年份:2016
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Intervening with Latent HIV-1 Infection using Gnidimacrin
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8658778 - 财政年份:2014
- 资助金额:
$ 52.44万 - 项目类别:
Intervening with Latent HIV-1 Infection using Gnidimacrin
使用 Gnidimacrin 干预潜伏性 HIV-1 感染
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8828549 - 财政年份:2014
- 资助金额:
$ 52.44万 - 项目类别:
Small Molecules that Regulate Proteasome Activity
调节蛋白酶体活性的小分子
- 批准号:
7939288 - 财政年份:2009
- 资助金额:
$ 52.44万 - 项目类别:
Small Molecules that Regulate Proteasome Activity
调节蛋白酶体活性的小分子
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7748967 - 财政年份:2009
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Small Molecules that Regulate Proteasome Activity
调节蛋白酶体活性的小分子
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8204613 - 财政年份:2009
- 资助金额:
$ 52.44万 - 项目类别:
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