【摘 要】
：
Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role
【机 构】
：
Center for Drug Design,College of Pharmacy,University of Minnesota,Minneapolis,MN 55455,USA
论文部分内容阅读
Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical out-comes of RDV could be largely underestimated.We performed an in vitro and in vivo drug metabolism and phar-macokinetics (DMPK) assessment to examine the potential of RDV,and particularly GS-441524,as oral drugs.In our in vitro assessments,RDV exhibited prohibitively low stability in human liver microsomes (HLMs,t1/2 =～ 1 min),with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphor-amidate moiety.This observation is poorly aligned with any potential oral use of RDV,though in the presence of cobicistat,the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH.Conversely,GS-441524 showed excellent metabolic stability in human plasma and HLMs.In further in vivo studies in CD-1 mice,GS-441524 displayed a favorable oral bioavailability of 57％.Importantly,GS-441524 produced adequate drug exposure in the mice plasma and lung,and was effectively converted to the active triphosphate,suggesting that it could be a promising oral antiviral drug for treating COVID-19.
其他文献
Nature has endowed gaseous molecules such as O2,CO2,CO,NO,H2S,and N2 with critical and diverse roles in sustaining life,from supplying energy needed to power life and building blocks for life\'s physical structure to mediating and coordinating cellular
The recent discovery of activator compounds binding to an allosteric site on the NAD+-dependent protein lysine deacetylase,sirtuin 6(SIRT6)has attracted interest and presents a pharmaceu-tical target for aging-related and cancer diseases.However,the mecha
HYD-PEP06,an endostatin-modified polypeptide,has been shown to produce effective anti-colorectal carcinoma effects through inhibiting epithelial--mesenchymal transition (EMT).However,whether HYD-PEP06 has similar suppressive effect on hepatocellular carci
Over the past decade,traditional Chinese medicine (TCM) has widely embraced systems biology and its various data integration approaches to promote its modernization.Thus,integrative pharmacology-based traditional Chinese medicine (TCMIP) was proposed as a
IF1 (ATPIF1) is a nuclear DNA-encoded mitochondrial protein whose activity is inhibition of the F1Fo-ATP synthase to control ATP production.IF1 activity remains unknown in the regulation of GLP-1 activity.In this study,IF1 was examined in the diet-induced
As one of the most lethal diseases,pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities.Furthermore,pancreatic cancer escapes early detection dur-ing the curable period because early symptoms rarely emerge an
The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous,ATP-dependent molec-ular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates.Because many of these clients are overexpressed or bec
Macrophages are typically identified as classically activated (M1) macrophages and alterna-tively activated (M2) macrophages,which respectively exhibit pro-and anti-inflammatory phenotypes,and the balance between these two subtypes plays a critical role i
Limb and CNS expressed 1 like (LIX1L) is over-expressed in several types of tumors.How-ever,the function of LIX1L in glucose metabolism and hepatocellular carcinoma (HCC) progression re-mains elusive.Here we report that LIX1L is over-expressed in human HC
Fusidane-type antibiotics,represented by helvolic acid,fusidic acid and cephalosporin P1,are fungi-derived antimicrobials with little cross-resistance to co mmonly used antibiotics.Generation of new fusidane-type derivatives is therefore of great value,bu