The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ...The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.展开更多
The N-methyl-d-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion channels.Within the various subtypes of NMDA receptors,the GluN1/2A subtype plays a si...The N-methyl-d-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion channels.Within the various subtypes of NMDA receptors,the GluN1/2A subtype plays a significant role in central nervous system(CNS)disorders.The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors,encompassing negative allosteric modulators(NAMs),positive allosteric modulators(PAMs)and competitive antagonists.Moreover,the ligands’structure–activity relationships(SARs)and the binding models of representative ligands are also discussed,providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.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
Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety pr...Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.展开更多
HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, ...HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.展开更多
Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a s...Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.展开更多
Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 ...Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.展开更多
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(NNI...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 a2.The 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 mutations.Especially,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 investigated.Furthermore,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.展开更多
Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show rece...Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding poses.Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action studies.Current and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging progress.However,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire process.This part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine residues.Recent studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase activities.Here,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on its concentration,optimal levels of NO in cancer cells is desirable.In this minireview,we briefly describe recent advances in the research of NO-based anticancer agents by our group and present some opinions on the future development of these agents.(H)The field of photoactivation strategies have been extensively developed for controlling chemical and biological processes with light.This review will summarize and provide insight into recent research advances in the understanding of photoactivatable molecules including photoactivatable caged prodrugs and photoswitchable molecules.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is ...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.展开更多
Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY)...Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.展开更多
Various boron-containing drugs have been approved for clinical use over the past two decades,and more are currently in clinical trials.The increasing interest in boron-containing compounds is due to their unique bindi...Various boron-containing drugs have been approved for clinical use over the past two decades,and more are currently in clinical trials.The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets;for example,boron substitution can be used to modulate biological activity,pharmacokinetic properties,and drug resistance.In this perspective,we aim to comprehensively review the current status of boron compounds in drug discovery,focusing especially on progress from 2015 to December 2020.We classify these compounds into groups showing anticancer,antibacterial,antiviral,antiparasitic and other activities,and discuss the biological targets associated with each activity,as well as potential future developments.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is ...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.展开更多
基金We gratefully acknowledge financial support from Major Basic Research Project of Shandong Provincial Natural Science Foundation(ZR2021ZD17,China)Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)+4 种基金Foreign Cultural and Educational Experts Project(GXL20200015001,China)Guangdong Basic and Applied Basic Research Foundation(2021A1515110740,China)China Postdoctoral Science Foundation(2021M702003)This work was supported in part by the Ministry of Science and Innovation of Spain through grant PID2019-104176RBI00/AEI/10.13039/501100011033 awarded to Luis Menéndez-AriasAn institutional grant of the Fundación Ramón Areces(Madrid,Spain)to the CBMSO is also acknowledged.Luis Menéndez-Arias is member of the Global Virus Network.
文摘The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.
基金The work was supported by the National Natural Science Foundation of China(82204200)the International Postdoctoral Exchange Fellowship Program(Talent-Introduction Program,YJ20210279,China)+1 种基金the China Postdoctoral Science Foundation(2022M711939)to Fabao Zhao,and the Natural Science Foundation of Shandong Province(ZR2022QH287 to Fabao Zhao and ZR2022QH312 to Na Liu,China).
文摘The N-methyl-d-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion channels.Within the various subtypes of NMDA receptors,the GluN1/2A subtype plays a significant role in central nervous system(CNS)disorders.The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors,encompassing negative allosteric modulators(NAMs),positive allosteric modulators(PAMs)and competitive antagonists.Moreover,the ligands’structure–activity relationships(SARs)and the binding models of representative ligands are also discussed,providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.
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financial support from Natural Science Foundation of China (81974507)Guangdong Basic and Applied Basic Research Foundation (2021A1515110740, China)+5 种基金China Postdoctoral Science Foundation (2021M702003)Shandong Province Natural Science Foundation for Youths (ZR2022QH036, China)the Foundation for Innovative Research Groups of State Key Laboratory of Microbial Technology (WZCX2021-03, China)Foreign cultural and educational experts Project (GXL20200015001, China)Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31, China)the Shandong Provincial Key research and development project (2019JZZY021011, China)。
文摘Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.82173677,81773574)the Key Project of NSFC for International Cooperation(No.81420108027)+2 种基金the Shandong Provincial Key Research and Development Project(No.2019JZZY021011)the Science Foundation for Outstanding Young Scholars of Shandong Province(No.ZR2020JQ31)NIH/NIAID grant(No.R01AI150491,Cocklin,PI,Salvino,Co-I)。
文摘HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.81973181,82273773)Shandong Provincial Natural Science Foundation(Nos.ZR2020YQ61,ZR2020JQ31)Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province。
文摘Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.
基金financial support from the Shandong Provincial Key Research and Development Project(No.2019JZZY021011,China)Foreign Cultural and Educational Experts Project(GXL20200015001,China)+1 种基金Outstanding Youth Fund of Shandong Province(ZR2020JQ31,China)Qilu Young Scholars Program of Shandong University and the Taishan Scholar Program at Shandong Province。
文摘Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.
基金financial support from the Key Project of NSFC for International Cooperation(No.81420108027,China)the National Natural Science Foundation of China(NSFC Nos.81273354,81573347,81903453)+6 种基金Young Scholars Program of Shandong University(YSPSDU No.2016WLJH32,China)Shandong Provincial Natural Science Foundation(ZR2019BH011,China)China Postdoctoral Science Foundation(2018M640641,2019T120596)Key research and development project of Shandong Province(No.2017CXGC1401,China)KU Leuven(GOA 10/014,Belgium)the Spanish Government(MINECO Project SAF2017-881074-R,AEI/FEDER,UE)Generalitat de Catalunya(2017SGR1746,Spain)for the financial support
文摘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 a2.The 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 mutations.Especially,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 investigated.Furthermore,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.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81973173 and 81773571),Jiangsu Province Funds for Excellent Young Scientists(No.BK20170088),the Six Talent Peaks Project(No.YY-023)and the 333 Project of Jiangsu Province.
文摘Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding poses.Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action studies.Current and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging progress.However,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire process.This part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine residues.Recent studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase activities.Here,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on its concentration,optimal levels of NO in cancer cells is desirable.In this minireview,we briefly describe recent advances in the research of NO-based anticancer agents by our group and present some opinions on the future development of these agents.(H)The field of photoactivation strategies have been extensively developed for controlling chemical and biological processes with light.This review will summarize and provide insight into recent research advances in the understanding of photoactivatable molecules including photoactivatable caged prodrugs and photoswitchable molecules.
基金supported by grants from the COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W)grants from the Natural Science Foundation of Jiangsu Province(SBK2020042706 to P.-H.W)+3 种基金grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G.,and the Fundamental Research Funds of Shandong University(21510078614099)the Fundamental Research Funds of Cheeloo College of Medicine(21510089393109)China Postdoctoral Science Foundation(2018M642662)the Natural Science Foundation of China(81901604)awarded to Y.Z.,and grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.
基金financial support from the National Natural Science Foundation of China (Nos. 81973181, 81903453)Shandong Provincial Natural Science Foundation (No. ZR2019BH011)+7 种基金Natural Science Foundation of Jiangsu Province (No. BK2019041035)China Postdoctoral Science Foundation (Nos. 2019T120596, 2018M640641)Science Foundation for Outstanding Young Scholars of Shandong Province (No. ZR2020JQ31)Science Foundation for Excellent Young Scholars of Shandong Province (No. ZR2020YQ61)National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2019ZX09301126)Shandong Provincial Key Research and Development Project (Nos. 2017CXGC1401, 2019JZZY021011)Foreign cultural and educational experts Project (No. GXL20200015001)the Taishan Scholar Program at Shandong Province and KU Leuven (No. GOA 10/014)。
文摘Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.
基金Financial support from the National Natural Science Foundation of China(No.81973181,to Xinyong Liu,China)Shandong Provincial Key Research and Development Project(No.2019JZZY021011,to Peng Zhan,China)+5 种基金National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(2019ZX09301126,to Xinyong Liu,China)Outstanding Youth Fund of Shandong Province(ZR2020JQ31,to Peng Zhan,China)Foreign Cultural and Educational Experts Project(GXL20200015001,to Xinyong Liu,China)the Program for Outstanding Ph.D.Candidate of Shandong University(to Lin Sun,China)Qilu Young Scholars Program of Shandong University(to Peng Zhan,China)the Taishan Scholar Program at Shandong Province(to Xinyong Liu,China)。
文摘Various boron-containing drugs have been approved for clinical use over the past two decades,and more are currently in clinical trials.The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets;for example,boron substitution can be used to modulate biological activity,pharmacokinetic properties,and drug resistance.In this perspective,we aim to comprehensively review the current status of boron compounds in drug discovery,focusing especially on progress from 2015 to December 2020.We classify these compounds into groups showing anticancer,antibacterial,antiviral,antiparasitic and other activities,and discuss the biological targets associated with each activity,as well as potential future developments.
基金This work was supported by grants from the COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W)grants from the Natural Science Foundation of Jiangsu Province(SBK2020042706 to P.-H.W)+5 种基金grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G.the Fundamental Research Funds of Shandong University(21510078614099)the Fundamental Research Funds of Cheeloo College of Medicine(21510089393109)China Postdoctoral Science Foundation(2018M642662)the Natural Science Foundation of China(81901604)awarded to Y.Z.grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.