tetano
Editor, Senior Moderator
FEBS J
. 2025 Jan 2.
doi: 10.1111/febs.17380. Online ahead of print. Psoralidin acts as a dual protease inhibitor against PL[SUP]pro[/SUP] and M[SUP]pro[/SUP] of SARS-CoV-2
Aditya Trivedi[SUP] 1 [/SUP], Tushar Kushwaha[SUP] 2 [/SUP], Ishani[SUP] 1 [/SUP], Sudhanshu Vrati[SUP] 3 [/SUP], Dharmender Gupta[SUP] 3 [/SUP], Sarala Rani Kayampeta[SUP] 4 [/SUP], Mohammad Khalid Parvez[SUP] 5 [/SUP], Krishna Kishore Inampudi[SUP] 2 [/SUP], Mohan Babu Appaiahgari[SUP] 6 7 [/SUP], Deepak Sehgal[SUP] 1 [/SUP]
Affiliations
The emergence of new coronavirus variants and concerns about vaccine effectiveness against these novel variants emphasize the need for broad-spectrum therapeutics targeting conserved coronaviral non-structural proteins. Accordingly, a virtual library of 178 putative inhibitors targeting SARS-CoV-2 Papain-like protease (PL[SUP]pro[/SUP]) was compiled through a systematic review of published literature and subsequently screened using molecular docking. Selected hits were analyzed for protease inhibitory activities, binding strength, and antiviral activities against HCoV229E-based surrogate system and subsequently against SARS-CoV-2 for validation. Differences in potential modes of action were investigated using an HCoV229E-based system, combined with in silico and biophysical methods against SARS-CoV-2 system. Of the 178 hits, 13 molecules showed superior docking scores against PL[SUP]pro[/SUP] and met the inclusion criteria for further investigations. Of these, seven showed notable inhibitory activities against PL[SUP]pro[/SUP]. Particularly, both Psoralidin and Corylifol-A exhibited superior and, importantly, dual activities against SARS-CoV-2 M[SUP]pro[/SUP]. Both molecules were found to be biologically active against HCoV229E and SARS-CoV-2; however, Psoralidin exhibited more consistent effects and was relatively well-tolerated. Detailed in silico analyses of their interactions with the two proteases identified differences in their modes of action, primarily due to differences in their binding of PL[SUP]pro[/SUP]. Based on these findings, we propose Psoralidin as a potential candidate for further development as a broad-spectrum antiviral and Corylifol-A as an ideal candidate for lead optimization.
Keywords: HCoV‐229E; PLpro; Psoralidin; SARS‐CoV‐2; in vitro.
. 2025 Jan 2.
doi: 10.1111/febs.17380. Online ahead of print. Psoralidin acts as a dual protease inhibitor against PL[SUP]pro[/SUP] and M[SUP]pro[/SUP] of SARS-CoV-2
Aditya Trivedi[SUP] 1 [/SUP], Tushar Kushwaha[SUP] 2 [/SUP], Ishani[SUP] 1 [/SUP], Sudhanshu Vrati[SUP] 3 [/SUP], Dharmender Gupta[SUP] 3 [/SUP], Sarala Rani Kayampeta[SUP] 4 [/SUP], Mohammad Khalid Parvez[SUP] 5 [/SUP], Krishna Kishore Inampudi[SUP] 2 [/SUP], Mohan Babu Appaiahgari[SUP] 6 7 [/SUP], Deepak Sehgal[SUP] 1 [/SUP]
Affiliations
- PMID: 39745898
- DOI: 10.1111/febs.17380
The emergence of new coronavirus variants and concerns about vaccine effectiveness against these novel variants emphasize the need for broad-spectrum therapeutics targeting conserved coronaviral non-structural proteins. Accordingly, a virtual library of 178 putative inhibitors targeting SARS-CoV-2 Papain-like protease (PL[SUP]pro[/SUP]) was compiled through a systematic review of published literature and subsequently screened using molecular docking. Selected hits were analyzed for protease inhibitory activities, binding strength, and antiviral activities against HCoV229E-based surrogate system and subsequently against SARS-CoV-2 for validation. Differences in potential modes of action were investigated using an HCoV229E-based system, combined with in silico and biophysical methods against SARS-CoV-2 system. Of the 178 hits, 13 molecules showed superior docking scores against PL[SUP]pro[/SUP] and met the inclusion criteria for further investigations. Of these, seven showed notable inhibitory activities against PL[SUP]pro[/SUP]. Particularly, both Psoralidin and Corylifol-A exhibited superior and, importantly, dual activities against SARS-CoV-2 M[SUP]pro[/SUP]. Both molecules were found to be biologically active against HCoV229E and SARS-CoV-2; however, Psoralidin exhibited more consistent effects and was relatively well-tolerated. Detailed in silico analyses of their interactions with the two proteases identified differences in their modes of action, primarily due to differences in their binding of PL[SUP]pro[/SUP]. Based on these findings, we propose Psoralidin as a potential candidate for further development as a broad-spectrum antiviral and Corylifol-A as an ideal candidate for lead optimization.
Keywords: HCoV‐229E; PLpro; Psoralidin; SARS‐CoV‐2; in vitro.