tetano
Editor, Senior Moderator
FEBS Open Bio
. 2025 Jul 1.
doi: 10.1002/2211-5463.70082. Online ahead of print. NMR screening of low molecular weight inhibitors targeting the papain-like protease (PLPro) of SARS-CoV-2
Dennis J Pyper[SUP] 1 [/SUP], Sridhar Sreeramulu[SUP] 1 [/SUP], Benjamin T Lanham[SUP] 2 [/SUP], Elizabeth M Engle[SUP] 2 [/SUP], David Fushman[SUP] 2 [/SUP], Harald Schwalbe[SUP] 1 [/SUP]
Affiliations
The Papain-like protease (PLPro) from SARS-CoV-2 plays an important role in the cleavage of the polyproteins Pp1a and Pp1ab as well as in the suppression of the immune response by deISG15ylation. Considerable effort is therefore devoted to developing low molecular weight inhibitors as starting points for antiviral drugs. Here, we present the results of an NMR screening study of PLPro for binding to the DSI-poised fragment library containing 607 compounds. Based on saturation-transfer difference (STD)- and WaterLOGSY-NMR experiments, we identified 86 binding compounds. We prioritized five candidates for further in-depth analysis. For three of those, we determined dissociation constants and two distinct binding sites on PLPro. These compounds could serve as a basis for future drug design studies in medicinal chemistry.
Keywords: NMR spectroscopy; Nsp3d; SARS‐CoV‐2; coronavirus; fragment‐based NMR screening; papain‐like protease PLPro.
. 2025 Jul 1.
doi: 10.1002/2211-5463.70082. Online ahead of print. NMR screening of low molecular weight inhibitors targeting the papain-like protease (PLPro) of SARS-CoV-2
Dennis J Pyper[SUP] 1 [/SUP], Sridhar Sreeramulu[SUP] 1 [/SUP], Benjamin T Lanham[SUP] 2 [/SUP], Elizabeth M Engle[SUP] 2 [/SUP], David Fushman[SUP] 2 [/SUP], Harald Schwalbe[SUP] 1 [/SUP]
Affiliations
- PMID: 40598773
- DOI: 10.1002/2211-5463.70082
The Papain-like protease (PLPro) from SARS-CoV-2 plays an important role in the cleavage of the polyproteins Pp1a and Pp1ab as well as in the suppression of the immune response by deISG15ylation. Considerable effort is therefore devoted to developing low molecular weight inhibitors as starting points for antiviral drugs. Here, we present the results of an NMR screening study of PLPro for binding to the DSI-poised fragment library containing 607 compounds. Based on saturation-transfer difference (STD)- and WaterLOGSY-NMR experiments, we identified 86 binding compounds. We prioritized five candidates for further in-depth analysis. For three of those, we determined dissociation constants and two distinct binding sites on PLPro. These compounds could serve as a basis for future drug design studies in medicinal chemistry.
Keywords: NMR spectroscopy; Nsp3d; SARS‐CoV‐2; coronavirus; fragment‐based NMR screening; papain‐like protease PLPro.