The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy.Moreover,after more than 2 years,many populations are still under pressure of infection.Thus,a broad...The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy.Moreover,after more than 2 years,many populations are still under pressure of infection.Thus,a broader perspective in developing antiviral strategies is still of great importance.Inspired by the observed multiple benefits of heparin in the treatment of thrombosis,the potential of low molecular weight heparin(LMWH)for the treatment of COVID-19 have been explored.Clinical applications found that LMWH decreased the level of inflammatory cytokines in COVID-19 patients,accordingly reducing lethality.Furthermore,several in vitro studies have demonstrated the important roles of heparan sulfate in SARS-CoV-2 infection and the inhibitory effects of heparin and heparin mimetics in viral infection.These clinical observations and designed studies argue for the potential to develop heparin mimetics as anti-SARS-CoV-2 drug candidates.In this review,we summarize the properties of heparin as an anticoagulant and the pharmaceutical possibilities for the treatment of virus infection,focusing on the perspectives of developing heparin mimetics via chemical synthesis,chemoenzymatic synthesis,and bioengineered production by microbial cell factories.The ultimate goal is to pave the eminent need for exploring novel compounds to treat coronavirus infection-caused diseases.展开更多
Cordycepin(3′-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro a...Cordycepin(3′-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro and in vivo remain vague. In this study, we reported functional target molecule of cordycepin which inhibited pancreatic cancer cells growth in vitro and in vivo.Cordycepin was confirmed to induce apoptosis by activating caspase-3, caspase-9 and cytochrome c. Further studies suggested that MAPK pathway was blocked by cordycepin via inhibiting the expression of Ras and the phosphorylation of Erk. Moreover, cordycepin caused S-phase arrest and DNA damage associated with activating Chk2(checkpoint kinase 2) pathway and downregulating cyclin A2 and CDK2 phosphorylation. Very interestingly, we showed that cordycepin could bind to FGFR2(KD = 7.77 × 10-9) very potently to inhibit pancreatic cancer cells growth by blocking Ras/Er K pathway. These results suggest that cordycepin could potentially be a leading compound which targeted FGFR2 to inhibit pancreatic cells growth by inducing cell apoptosis and causing cell cycle arrest via blocking FGFR/Ras/ERK signaling for anti-pancreatic cancer new drug development.展开更多
基金support from the National Key Research and Development Program of China (2021YFF0600700,2020YFA090032 and 2019YFA0906201)the Swedish research council (2020-05759)the National Natural Science Foundation of China (31720103901,31961133004,21907031,21977029,22108266).
文摘The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy.Moreover,after more than 2 years,many populations are still under pressure of infection.Thus,a broader perspective in developing antiviral strategies is still of great importance.Inspired by the observed multiple benefits of heparin in the treatment of thrombosis,the potential of low molecular weight heparin(LMWH)for the treatment of COVID-19 have been explored.Clinical applications found that LMWH decreased the level of inflammatory cytokines in COVID-19 patients,accordingly reducing lethality.Furthermore,several in vitro studies have demonstrated the important roles of heparan sulfate in SARS-CoV-2 infection and the inhibitory effects of heparin and heparin mimetics in viral infection.These clinical observations and designed studies argue for the potential to develop heparin mimetics as anti-SARS-CoV-2 drug candidates.In this review,we summarize the properties of heparin as an anticoagulant and the pharmaceutical possibilities for the treatment of virus infection,focusing on the perspectives of developing heparin mimetics via chemical synthesis,chemoenzymatic synthesis,and bioengineered production by microbial cell factories.The ultimate goal is to pave the eminent need for exploring novel compounds to treat coronavirus infection-caused diseases.
基金Strategic Priority Research Program of the Chinese Academy of Sciences (No.XDA12010302)National Natural Science Foundation of China(No. 31230022)Program of Shanghai Subject Chief Scientist(No. 16XD1404500)。
文摘Cordycepin(3′-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro and in vivo remain vague. In this study, we reported functional target molecule of cordycepin which inhibited pancreatic cancer cells growth in vitro and in vivo.Cordycepin was confirmed to induce apoptosis by activating caspase-3, caspase-9 and cytochrome c. Further studies suggested that MAPK pathway was blocked by cordycepin via inhibiting the expression of Ras and the phosphorylation of Erk. Moreover, cordycepin caused S-phase arrest and DNA damage associated with activating Chk2(checkpoint kinase 2) pathway and downregulating cyclin A2 and CDK2 phosphorylation. Very interestingly, we showed that cordycepin could bind to FGFR2(KD = 7.77 × 10-9) very potently to inhibit pancreatic cancer cells growth by blocking Ras/Er K pathway. These results suggest that cordycepin could potentially be a leading compound which targeted FGFR2 to inhibit pancreatic cells growth by inducing cell apoptosis and causing cell cycle arrest via blocking FGFR/Ras/ERK signaling for anti-pancreatic cancer new drug development.