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
Objective This study aimed to investigate the expression and significance of PIN2/TERF1 interacting, telomerase inhibitor 1(Pin X1) and human telomerase reverse transcriptase(h TERT) in basal cell carcinoma(BCC). Meth...Objective This study aimed to investigate the expression and significance of PIN2/TERF1 interacting, telomerase inhibitor 1(Pin X1) and human telomerase reverse transcriptase(h TERT) in basal cell carcinoma(BCC). Methods Real-time polymerase chain reaction and immunohistochemistry were performed to quantify the m RNA expressions and integrated optical density(IOD), respectively, of Pin X1 and h TERT in BCC specimens(n = 30), as well as in normal skin specimens(n = 15). Results The m RNA expression level and IOD of Pin X1 in the BCC samples were both significantly lower than those in the control specimens(P < 0.05). Conversely, the m RNA expression level and IOD of h TERT in BCC were both significantly higher than that in the control samples(P < 0.05). The correlation between the expression levels of Pin X1 and h TERT showed no statistical significance(P > 0.05). Conclusion Downregulation of Pin X1 and upregulation of h TERT expression may be associated with the activation and maintenance of telomerases in the induction of BCC.展开更多
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.
文摘Objective This study aimed to investigate the expression and significance of PIN2/TERF1 interacting, telomerase inhibitor 1(Pin X1) and human telomerase reverse transcriptase(h TERT) in basal cell carcinoma(BCC). Methods Real-time polymerase chain reaction and immunohistochemistry were performed to quantify the m RNA expressions and integrated optical density(IOD), respectively, of Pin X1 and h TERT in BCC specimens(n = 30), as well as in normal skin specimens(n = 15). Results The m RNA expression level and IOD of Pin X1 in the BCC samples were both significantly lower than those in the control specimens(P < 0.05). Conversely, the m RNA expression level and IOD of h TERT in BCC were both significantly higher than that in the control samples(P < 0.05). The correlation between the expression levels of Pin X1 and h TERT showed no statistical significance(P > 0.05). Conclusion Downregulation of Pin X1 and upregulation of h TERT expression may be associated with the activation and maintenance of telomerases in the induction of BCC.
