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作者： samuel desta 山东大学

学位级别：硕士

Acquired immune deficiency syndrome（AIDS）,mainly caused by human immunodeficiency virus type-1（HIV-1）,is still one of the leading causes of death *** highly active antiretroviral therapy（HAART）regimens,a combination of three or more HIV-1 antiretroviral targeting different steps of active viral replication,is used as the most efficient treatment regimen in controlling HIV-1 replication in infected ***-nucleoside reverse transcriptase inhibitors（NNRTIs）comprise an important component of HAART,owing to their potent antiviral activity,high selectivity and generally good ***,the efficacy of NNRTIs is compromised by the emergence of drug-resistant mutations,poor pharmacokinetic properties and severe toxic side effects over long-term *** impose the development of new NNRTIs with broader antiviral spectrum and better pharmacokinetic *** induce conformational change of the active site by binding to HIV-1 reverse transcriptase at a site distinct from the DNA polymerase active site of the enzyme,and inhibit retroviral reverse transcription step of HIV-1 replication in a non-competitive *** the past few years,diarylpyrimidine（DAPY）-based NNRTIs,represented by etravirine（ETR）and rilpivirine（RPV）,have attracted considerable attention because of their exceptional characteristics such as positional adaptability and conformational flexibility,which might serve to minimize the loss of binding stabilization caused by *** addition,the key hydrogen bonds and specifically targeting conserved residues of reverse transcriptase provide important avenues for further optimization and development of anti-HIV drug *** thesis has two *** Ⅰ.Design,Synthesis and Biological Evaluation of Piperidine-linked Quinazoline Derivatives as Potent HIV-1 NNRTIsBy employing molecular hybridization and scaffold hopping strategy,the two tolerant regions of non-nucleoside inhibitory binding pocket（NNIBP）were explor

关键词： NNRTIs Quinazoline Drug resistance HIV-1 Latent reservoirs LRAs HDACIs

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Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidinesubstituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs

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Acta Pharmaceutica Sinica B 2020年第5期10卷 878-894,952页

作者： Dongwei Kang Da Feng Tiziana Ginex Jinmi Zou Fenju Wei Tong Zhao Boshi Huang Yanying Sun samuel desta Erik DeClercq Christophe Pannecouque Peng Zhan Xinyong Liu Department of Medicinal Chemistry Key Laboratory of Chemical BiologyMinistry of EducationSchool of Pharmaceutical SciencesShandong UniversityJinan 250012China Rega Institute for Medical Research Laboratory of Virology and ChemotherapyK.U.LeuvenLeuven B-3000Belgium Department of Nutrition Food Science and GastronomyFaculty of PharmacyCampus TorriberaInstitute of Biomedicine and Institute of Theoretical and Computational ChemistryUniversity of BarcelonaSanta Coloma de Gramenet 08921Spain

In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNIBP)by incorporating an aromatic moiety to the left wing of the lead K-5 *** newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase(RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors(NNRTI)-resistant ***,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations(L1001,K103 N,Y181 C,Y188 L and E138 K)with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine(ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also ***,26 exhibited favorable pharmacokinetics(PK)profiles and with a bioavailability of 33.8%.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

关键词： HIV-1 NNRTIs NNIBP Thiophene[3,2-d]pyrimidine Hydrophobic channel

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以蛋白质-蛋白质相互作用为靶点的HIV抑制剂的研究进展

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药学学报 2019年第4期54卷 620-628页

作者：汪昭 desta samuel 康东伟展鹏刘新泳山东大学药学院药物化学研究所化学生物学教育部重点实验室山东济南250012

蛋白质-蛋白质相互作用(protein-protein interaction, PPI)在人免疫缺陷病毒(human immunodeficiency virus, HIV)生命周期中的多个阶段发挥重要作用。针对这些相互作用特别是HIV与宿主细胞之间的相互作用为我们研发靶向于新结合位点... 详细信息

蛋白质-蛋白质相互作用(protein-protein interaction, PPI)在人免疫缺陷病毒(human immunodeficiency virus, HIV)生命周期中的多个阶段发挥重要作用。针对这些相互作用特别是HIV与宿主细胞之间的相互作用为我们研发靶向于新结合位点和具有新作用机制的HIV抑制剂提供了新思路。因此本综述基于多种蛋白质-蛋白质相互作用的作用机制,结合具体研究实例阐述了该类抑制剂的最新研究进展。

关键词：艾滋病 HIV 蛋白质-蛋白质相互作用抑制剂

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