RESUMO
This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.
Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , Desenho de Fármacos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Coronavirus disease (COVID-19) patients exhibit different patterns of liver impairment, according to growing evidence. AIM: In this study, we sought to provide a comprehensive analysis of liver test parameters in patients with severe and non-severe COVID-19. METHODS: We performed a meta-analysis of published liver manifestations and described the liver damage in COVID-19. We searched PubMed, Google Scholar, Embase, Cochrane Library, medRxiv, bioRxiv, and three Chinese electronic databases through April 18, 2020, in accordance with the Preferred Reporting Items for Meta-Analyses. We analyzed pooled data on liver chemistries stratified by COVID-19 severity using a fixed or random-effects model. RESULTS: A meta-analysis of 56 studies, including 11052 patients, found that the pooled mean alanine aminotransferase (ALT) in severe COVID-19 cases was 35.9 IU/L whereas in non-severe COVID-19 cases was 27.3 IU/L. Average aspartate aminotransferase (AST) levels were 44.3 IU/L in severe cases compared to 27.9 IU/L in non-severe cases. In addition, AST levels are often higher than ALT levels regardless of disease severity. The severe cases tended to have a higher gamma-glutamyltransferase level but a lower albumin level than the non-severe cases. CONCLUSION: Severe COVID-19 was more likely to be associated with abnormal liver test results. Monitoring liver chemistry closely can help detect disease progression early.
RESUMO
Although abnormal liver chemistries are linked to a higher risk of coronavirus disease 2019 (COVID-19)-related death, liver manifestations may be diverse and even confusing. Thus, we performed a meta-analysis of published liver manifestations and described the liver damage in patients with COVID-19 who died or discharged alive. We searched PubMed, Google Scholar, medRxiv, bioRxiv, the Cochrane Library, Embase, and three Chinese electronic databases through April 22, 2020. We analyzed pooled data on liver chemistries stratified by the main clinical outcome of COVID-19, using a fixed or random-effects model. In our meta-analysis of 19 studies, which included a total of 4,103 patients, the pooled mean alanine aminotransferase and aspartate aminotransferase levels were, respectively, 31.7 IU/L and 51.0 IU/L in the patients with COVID-19 who died and 27.7 IU/L and 32.9 IU/L in those discharged alive (both P < 0.0001). Compared with the patients discharged alive, those who died tended to have lower albumin levels but longer prothrombin time and higher international normalized ratio. Conclusion: In this meta-analysis, according to the main clinical outcome of COVID-19, we comprehensively describe three patterns of liver impairment related to COVID-19: hepatocellular injury, cholestasis, and hepatocellular disfunction. The patients who died from COVID-19 tended to have different liver chemistries from those discharged alive. Special caution should be given to the patients with a relatively higher index of liver chemistries.