以蛹虫草子实体为材料,经水提醇沉后获得沉淀样品 P 和上清样品 L,初步抗 HIV-1蛋白酶检测显示活性成份集中在样品 L 中.进一步利用大孔吸附树脂和高压液相对 L 进行分离纯化,并对纯化样品的体外抗HIV-1蛋白酶活性和抗 HIV-1逆转录酶活...以蛹虫草子实体为材料,经水提醇沉后获得沉淀样品 P 和上清样品 L,初步抗 HIV-1蛋白酶检测显示活性成份集中在样品 L 中.进一步利用大孔吸附树脂和高压液相对 L 进行分离纯化,并对纯化样品的体外抗HIV-1蛋白酶活性和抗 HIV-1逆转录酶活性进行了测定.结果显示,L 经大孔吸附树脂和高压液相分离纯化后得到三种物质均具有抗 HIV-1蛋白酶活性 f1,f2和 f3,其中 f1对 HIV-1蛋白酶抑制作用最强,比 L 提高了约29%;三种物质对 HIV-1逆转录酶均有一定的抑制作用.展开更多
HIV-1 reverse transcriptase (RT) RNase H (HIV-RH) is a key target of anti-AIDS drugs. Metal-chelating compounds are an important class of chemicals in pharmacological drug discovery, especially in relation to HIV-RT a...HIV-1 reverse transcriptase (RT) RNase H (HIV-RH) is a key target of anti-AIDS drugs. Metal-chelating compounds are an important class of chemicals in pharmacological drug discovery, especially in relation to HIV-RT and the highly-related HIV-integrase. The correlation between the metal-chelating properties and enzyme activities of the metal chelators is always of high scientific interest, as an understanding of this may accelerate the rational optimization of this class of inhibitors. Our NMR data show that Mg2+ and Ca2+ bind specifically to the active site of the RNase H domain and two Mg2+ ions sequentially bind one molecule of RNase H. We also demonstrate here, using saturated and unsaturated tricyclic N-hydroxypyridones designed to block the active site, that the primary binding sites and affinities of divalent metal ions are correlated with the structures of the chelating motifs. Chemical shift perturbation studies of protein/metal-ion/compound ternary complexes also indicate that divalent metal ions play important roles for the specific interaction of the compounds with the RNase H active site.展开更多
With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To ...With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50values ranging from 3.43 to 21.4 nmol/L.Especially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.展开更多
Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reve...Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reversal agents(LRAs)to activate HIV latent reservoirs,followed by immunotherapy to remove infected cells.Immunomodulatory LRAs have the dual advantage of activating viral latency and promoting immune cell elimination of HIV-infected cells.The emergence of novel immunotherapies has also enhanced the possibility ofHIV clearance.Here we review the activity and potential mechanisms of immunomodulatory agonists and immunotherapies.The possible combinational strategies to achieve HIV functional cure and the problems encountered using this approach are discussed.展开更多
In this study,37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated,building upon our previous synthesis of 51 phorbol derivatives.12-Para-electron-acceptor-trans-cinnamoyl-13-dec...In this study,37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated,building upon our previous synthesis of 51 phorbol derivatives.12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out,demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation.These derivatives exhibited a higher safety index compared with the positive control drug.Among them,12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol,designated as compound 3c,exhibited the most potent anti-HIV-1 activity(EC_(50)2.9 nmol·L^(−1),CC50/EC_(50)11117.24)and significantly inhibited the formation of syncytium(EC_(50)7.0 nmol·L^(−1),CC50/EC_(50)4891.43).Moreover,compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor.Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C(PKC).Therefore,compound 3c emerges as a potential candidate for developing new anti-HIV drugs.展开更多
Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary appr...Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.展开更多
Lenacapavir,targeting the human immunodeficiency virus type-1(HIV-1)capsid,is the first-in-class antiretroviral drug recently approved for clinical use.The development of Lenacapavir is attributed to the remarkable pr...Lenacapavir,targeting the human immunodeficiency virus type-1(HIV-1)capsid,is the first-in-class antiretroviral drug recently approved for clinical use.The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years.Considered little more than a component of the virus shell to be shed early during infection,the capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host factors,entering the nucleus,and directing integration.Here,we describe the key advances that led to this‘capsid revolution’.展开更多
文摘以蛹虫草子实体为材料,经水提醇沉后获得沉淀样品 P 和上清样品 L,初步抗 HIV-1蛋白酶检测显示活性成份集中在样品 L 中.进一步利用大孔吸附树脂和高压液相对 L 进行分离纯化,并对纯化样品的体外抗HIV-1蛋白酶活性和抗 HIV-1逆转录酶活性进行了测定.结果显示,L 经大孔吸附树脂和高压液相分离纯化后得到三种物质均具有抗 HIV-1蛋白酶活性 f1,f2和 f3,其中 f1对 HIV-1蛋白酶抑制作用最强,比 L 提高了约29%;三种物质对 HIV-1逆转录酶均有一定的抑制作用.
文摘HIV-1 reverse transcriptase (RT) RNase H (HIV-RH) is a key target of anti-AIDS drugs. Metal-chelating compounds are an important class of chemicals in pharmacological drug discovery, especially in relation to HIV-RT and the highly-related HIV-integrase. The correlation between the metal-chelating properties and enzyme activities of the metal chelators is always of high scientific interest, as an understanding of this may accelerate the rational optimization of this class of inhibitors. Our NMR data show that Mg2+ and Ca2+ bind specifically to the active site of the RNase H domain and two Mg2+ ions sequentially bind one molecule of RNase H. We also demonstrate here, using saturated and unsaturated tricyclic N-hydroxypyridones designed to block the active site, that the primary binding sites and affinities of divalent metal ions are correlated with the structures of the chelating motifs. Chemical shift perturbation studies of protein/metal-ion/compound ternary complexes also indicate that divalent metal ions play important roles for the specific interaction of the compounds with the RNase H active site.
基金financial support from the National Natural Science Foundation of China(NSFC nos.81973181 and 81903453)Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)+6 种基金Science Foundation for Excellent Young Scholars of Shandong Province(ZR2020YQ61,China)Foreign Cultural and Educational Experts Project(GXL20200015001,China)China Postdoctoral Science Foundation(2022M721948)Shandong Province Natural Science Foundation for Youths(ZR2023QH217,China)Natural Science Foundation of Jiangsu Province(BK20230252,China)Qilu Young Scholars Program of Shandong UniversityTaishan Scholar Program at Shandong Province。
文摘With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50values ranging from 3.43 to 21.4 nmol/L.Especially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.
基金funded by the Beijing Municipal Science and Technology Commission(No.D17110700050000).
文摘Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reversal agents(LRAs)to activate HIV latent reservoirs,followed by immunotherapy to remove infected cells.Immunomodulatory LRAs have the dual advantage of activating viral latency and promoting immune cell elimination of HIV-infected cells.The emergence of novel immunotherapies has also enhanced the possibility ofHIV clearance.Here we review the activity and potential mechanisms of immunomodulatory agonists and immunotherapies.The possible combinational strategies to achieve HIV functional cure and the problems encountered using this approach are discussed.
基金supported by the National Natural Science Foundation of China(Nos.81202882,82060670)Suzhou Science and Technology Planning Project in Jiangsu Province of China(No.SNG2021022)+1 种基金the Priority Academic Program Development of the Jiangsu Higher Education Institutes,China(PAPD)and the Project of Innovative Research Team of Yunnan Province(No.202005AE160005).
文摘In this study,37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated,building upon our previous synthesis of 51 phorbol derivatives.12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out,demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation.These derivatives exhibited a higher safety index compared with the positive control drug.Among them,12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol,designated as compound 3c,exhibited the most potent anti-HIV-1 activity(EC_(50)2.9 nmol·L^(−1),CC50/EC_(50)11117.24)and significantly inhibited the formation of syncytium(EC_(50)7.0 nmol·L^(−1),CC50/EC_(50)4891.43).Moreover,compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor.Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C(PKC).Therefore,compound 3c emerges as a potential candidate for developing new anti-HIV drugs.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.20102007,29725203 and 20072042)the State Key Program of Basic Research of China(Grant No.2002CB512802)+1 种基金the 863 Hi-Tech Program of China(Grant Nos.2002AA233011,2002AA233061,2001AA235051 and 2001AA 235041)Foundation of Shanghai Ministry of Science and Technology,and the Key Program of New Drug Research and Development from the Chinese Academy of Sciences.
文摘Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.
基金supported by the UK Medical Research Council(MR/W001241/1 to A.F.)the Canadian Institute of Health Research(PJT-178127 to A.F.)+2 种基金the Francis Crick Institute(to I.A.T.),with core funding from Cancer Research UK(CC2029)the UK Medical Research Council(CC2029)the Wellcome Trust(CC2029).
文摘Lenacapavir,targeting the human immunodeficiency virus type-1(HIV-1)capsid,is the first-in-class antiretroviral drug recently approved for clinical use.The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years.Considered little more than a component of the virus shell to be shed early during infection,the capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host factors,entering the nucleus,and directing integration.Here,we describe the key advances that led to this‘capsid revolution’.
