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
Organizational resilience is vital to the survival and thriving of enterprises, especially during the COVID-19 pandemic. Although there has been an increasing interest in organizational resilience, the effects from the entrepreneur perspective receive scant attention. Based on upper echelons theory (UET) and personality psychology, we propose a model in which entrepreneurial mindfulness and entrepreneurial resilience could influence organizational resilience of SMEs. We empirically analyzed a sample of 180 entrepreneurs managing small- and medium-sized enterprises (SMEs) in China during the COVID-19 pandemic, using SmartPLS software. The research findings indicated that entrepreneurial mindfulness is positively associated with organizational resilience and such relationship is partially mediated by entrepreneurial resilience. These findings convey important theoretical implications in this field of research as well as practical implications for SMEs in China or other countries with similar nature.