7TZJ

SARS CoV-2 PLpro in complex with inhibitor 3k

Summary for 7TZJ

• Entry DOI: 10.2210/pdb7tzj/pdb
• Descriptor: Papain-like protease, N-[(3-fluorophenyl)methyl]-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: sars cov-2, papain-like protease, 3k, covid19, inhibitor, complex, hydrolase/inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 73381.32

Authors

Calleja, D.J.,Klemm, T.,Lechtenberg, B.C.,Kuchel, N.W.,Lessene, G.,Komander, D. (deposition date: 2022-02-15, release date: 2022-03-02, Last modification date: 2023-10-18)

Primary citation

Calleja, D.J.,Kuchel, N.,Lu, B.G.C.,Birkinshaw, R.W.,Klemm, T.,Doerflinger, M.,Cooney, J.P.,Mackiewicz, L.,Au, A.E.,Yap, Y.Q.,Blackmore, T.R.,Katneni, K.,Crighton, E.,Newman, J.,Jarman, K.E.,Call, M.J.,Lechtenberg, B.C.,Czabotar, P.E.,Pellegrini, M.,Charman, S.A.,Lowes, K.N.,Mitchell, J.P.,Nachbur, U.,Lessene, G.,Komander, D.
Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors.
Front Chem, 10:861209-861209, 2022

PubMed Abstract: The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, and , originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an SARS-CoV-2 infection model, justifying further optimization.

PubMed: 35494659
DOI: 10.3389/fchem.2022.861209

Experimental method

X-RAY DIFFRACTION (2.66 Å)