tetano
Editor, Senior Moderator
Chem Biol Drug Des
. 2022 Nov 11.
doi: 10.1111/cbdd.14179. Online ahead of print.
Design, Synthesis, and Biological Evaluation of Novel Ruxolitinib and Baricitinib Analogues for Potential Use Against COVID-19
Qin Lin[SUP] 1 [/SUP], Jun Li[SUP] 2 [/SUP], Yinping Wang[SUP] 1 [/SUP], Jie Zang[SUP] 3 [/SUP]
Affiliations
Abstract
The coronavirus pandemic known as COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), threatens public health worldwide. Approval of COVID-19 vaccines and antiviral drugs have greatly reduced the severe cases and mortality rate. However, the continues mutations of viruses are challenging the efficacies of vaccines and antiviral drugs. Drug repurposing campaign has identified two JAK1/2 inhibitors ruxolitinib and baricitinib as potential antiviral drugs. Ruxolitinib and baricitinib exerts dual antiviral effect by modulation of inflammatory response via JAK1/2 and inhibition of viral entry via AAK1 and GAK. Inspired by this, in an effort to diversify chemical space, three analogues ((R)-8, (S)-8 and 9) of ruxolitinib and baricitinb were made using scaffold hopping strategy. Compound 9 displayed potent and comparable potencies against AAK1, JAK1 and JAK2 compared to Baricitinib. Notably, compound 9 showed better selectivity for AAK1, JAK1 and JAK2 over GAK. Besides, compound 9 displayed good druglikeness according to Lipinski's and Veber's rule. We thereby identified a potential lead compound 9, which might be used for the further development of anti-coronaviral therapy.
Keywords: AP2-associated protein kinase 1 (AAK1); Cyclin G-associated kinase (GAK); Janus kinase (JAK); antiviral drugs; baricitinib; coronavirus disease 2019 (COVID-19); ruxolitinib.
. 2022 Nov 11.
doi: 10.1111/cbdd.14179. Online ahead of print.
Design, Synthesis, and Biological Evaluation of Novel Ruxolitinib and Baricitinib Analogues for Potential Use Against COVID-19
Qin Lin[SUP] 1 [/SUP], Jun Li[SUP] 2 [/SUP], Yinping Wang[SUP] 1 [/SUP], Jie Zang[SUP] 3 [/SUP]
Affiliations
- PMID: 36366971
- DOI: 10.1111/cbdd.14179
Abstract
The coronavirus pandemic known as COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), threatens public health worldwide. Approval of COVID-19 vaccines and antiviral drugs have greatly reduced the severe cases and mortality rate. However, the continues mutations of viruses are challenging the efficacies of vaccines and antiviral drugs. Drug repurposing campaign has identified two JAK1/2 inhibitors ruxolitinib and baricitinib as potential antiviral drugs. Ruxolitinib and baricitinib exerts dual antiviral effect by modulation of inflammatory response via JAK1/2 and inhibition of viral entry via AAK1 and GAK. Inspired by this, in an effort to diversify chemical space, three analogues ((R)-8, (S)-8 and 9) of ruxolitinib and baricitinb were made using scaffold hopping strategy. Compound 9 displayed potent and comparable potencies against AAK1, JAK1 and JAK2 compared to Baricitinib. Notably, compound 9 showed better selectivity for AAK1, JAK1 and JAK2 over GAK. Besides, compound 9 displayed good druglikeness according to Lipinski's and Veber's rule. We thereby identified a potential lead compound 9, which might be used for the further development of anti-coronaviral therapy.
Keywords: AP2-associated protein kinase 1 (AAK1); Cyclin G-associated kinase (GAK); Janus kinase (JAK); antiviral drugs; baricitinib; coronavirus disease 2019 (COVID-19); ruxolitinib.