Background:Albuvirtide is a once-weekly injectable human immunodeficiency virus(HIV)-1 fusion inhibitor.We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-riton...Background:Albuvirtide is a once-weekly injectable human immunodeficiency virus(HIV)-1 fusion inhibitor.We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.Methods:We carried out a 48-week,randomized,controlled,open-label non-inferiority trial at 12 sites in China.Adults on the World Health Organization(WHO)-recommended first-line treatment for>6 months with a plasma viral load>1000 copies/mL were enrolled and randomly assigned(1:1)to receive albuvirtide(once weekly)plus ritonavir-boosted lopinavir(ABT group)or the WHO-recommended second-line treatment(NRTI group).The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks.Non-inferiority was prespecified with a margin of 12%.Results:At the time of analysis,week 24 data were available for 83 and 92 patients,and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups,respectively.At 48 weeks,80.4%of patients in the ABT group and 66.0%of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL,meeting the criteria for non-inferiority.For the per-protocol population,the superiority of albuvirtide over NRTI was demonstrated.The frequency of grade 3 to 4 adverse events was similar in the two groups;the most common adverse events were diarrhea,upper respiratory tract infections,and grade 3 to 4 increases in triglyceride concentration.Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.Conclusions:The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug.This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.Trial registration:ClinicalTrials.gov Identifier:NCT02369965;https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No.ChiCTR-TRC-14004276;http://www.chictr.org.cn/enindex.aspx.展开更多
The development of broad-spectrum antivirals against human coronaviruses(HCoVs)is critical to combat the current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SAR...The development of broad-spectrum antivirals against human coronaviruses(HCoVs)is critical to combat the current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its variants,as well as future outbreaks of emerging CoVs.We have previously identified a polyethylene glycol-conjugated(PEGylated)lipopeptide,EK1C4,with potent pan-CoV fusion inhibitory activity.However,PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo.Therefore,we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment(HR2-CF)of HCoV-OC43.Among these lipopeptides,EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike(S)mutants,as well as other HCoVs and some bat SARS-related coronaviruses(SARSr-CoVs)tested.The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes,better metabolic stability in mouse serum,higher thermostability than the PEGylated lipopeptide EK1C4,suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.展开更多
HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusio...HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.展开更多
Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served a...Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.展开更多
基金Frontier Biotechnologies Inc.,Ministry of Science and Technology of China(Nos.2013ZX09101001 and 2017ZX09201007)the Beijing Municipal of Science and Technology Major Project(Nos.D141100000314005,D141100000314002,and D161100000416003)+1 种基金the National Natural Science Foundation of China(Nos.81772165,81974303,and 81571973)Beijing Key Laboratory for HIV/AIDS Research(No.BZ0089)。
文摘Background:Albuvirtide is a once-weekly injectable human immunodeficiency virus(HIV)-1 fusion inhibitor.We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.Methods:We carried out a 48-week,randomized,controlled,open-label non-inferiority trial at 12 sites in China.Adults on the World Health Organization(WHO)-recommended first-line treatment for>6 months with a plasma viral load>1000 copies/mL were enrolled and randomly assigned(1:1)to receive albuvirtide(once weekly)plus ritonavir-boosted lopinavir(ABT group)or the WHO-recommended second-line treatment(NRTI group).The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks.Non-inferiority was prespecified with a margin of 12%.Results:At the time of analysis,week 24 data were available for 83 and 92 patients,and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups,respectively.At 48 weeks,80.4%of patients in the ABT group and 66.0%of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL,meeting the criteria for non-inferiority.For the per-protocol population,the superiority of albuvirtide over NRTI was demonstrated.The frequency of grade 3 to 4 adverse events was similar in the two groups;the most common adverse events were diarrhea,upper respiratory tract infections,and grade 3 to 4 increases in triglyceride concentration.Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.Conclusions:The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug.This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.Trial registration:ClinicalTrials.gov Identifier:NCT02369965;https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No.ChiCTR-TRC-14004276;http://www.chictr.org.cn/enindex.aspx.
基金This work was supported by the National Natural Science Foundation of China(81822045 and 82041036 to Lu Lu,82041025 to Shibo Jiang,21877127 to Chao Wang)the Program of Shanghai Academic/Technology Research Leader(20XD1420300 to Lu Lu,China).
文摘The development of broad-spectrum antivirals against human coronaviruses(HCoVs)is critical to combat the current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its variants,as well as future outbreaks of emerging CoVs.We have previously identified a polyethylene glycol-conjugated(PEGylated)lipopeptide,EK1C4,with potent pan-CoV fusion inhibitory activity.However,PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo.Therefore,we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment(HR2-CF)of HCoV-OC43.Among these lipopeptides,EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike(S)mutants,as well as other HCoVs and some bat SARS-related coronaviruses(SARSr-CoVs)tested.The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes,better metabolic stability in mouse serum,higher thermostability than the PEGylated lipopeptide EK1C4,suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.
基金supported by the National Natural Science Foundation of China (No. 21602121)the Natural Science Foundation of Inner Mongolia (No. 2016BS0201)+2 种基金the Inner Mongolia Autonomous Region Higher School Youth scientific Talents Support Project(No. NJYT-17-B22)the Research Funds of Baotou Medical College(Nos. BSJJ201620, BYJJ-YF 201707)Beijing Tongzhou District Science and Technology Project(No. KJ2017CX039-14)
文摘HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.
文摘Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.
