9AZX

Crystal structure of SARS-CoV-2 (Covid-19) Nsp3 macrodomain in complex with NDPr

This is a non-PDB format compatible entry.

Summary for 9AZX

• Entry DOI: 10.2210/pdb9azx/pdb
• Descriptor: Non-structural protein 3, {(2R,3S,4R,5R)-5-[(8S)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-cyano-3,4-dihydroxyoxolan-2-yl}methyl [(2R,3S,4R,5R)-3,4,5-trihydroxyoxolan-2-yl]methyl dihydrogen diphosphate (3 entities in total)
• Functional Keywords: viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 3
• Total formula weight: 56577.32

Authors

Wallace, S.D.,Bagde, S.R.,Fromme, J.C. (deposition date: 2024-03-11, release date: 2024-05-01, Last modification date: 2024-05-29)

Primary citation

Peng, K.,Wallace, S.D.,Bagde, S.R.,Shang, J.,Anmangandla, A.,Jana, S.,Fromme, J.C.,Lin, H.
GS-441524-Diphosphate-Ribose Derivatives as Nanomolar Binders and Fluorescence Polarization Tracers for SARS-CoV-2 and Other Viral Macrodomains.
Acs Chem.Biol., 19:1093-1105, 2024

PubMed Abstract: Viral macrodomains that can bind to or hydrolyze protein adenosine diphosphate ribosylation (ADP-ribosylation) have emerged as promising targets for antiviral drug development. Many inhibitor development efforts have been directed against the severe acute respiratory syndrome coronavirus 2 macrodomain 1 (SARS-CoV-2 Mac1). However, potent inhibitors for viral macrodomains are still lacking, with the best inhibitors still in the micromolar range. Based on , a remdesivir precursor, and our previous studies, we have designed and synthesized potent binders of SARS-CoV-2 Mac1 and other viral macrodomains including those of Middle East respiratory syndrome coronavirus (MERS-CoV), Venezuelan equine encephalitis virus (VEEV), and Chikungunya virus (CHIKV). We show that the 1'-CN group of promotes binding to all four viral macrodomains tested while capping the 1″-OH of -diphosphate-ribose with a simple phenyl ring further contributes to binding. Incorporating these two structural features, the best binders show 20- to 6000-fold increases in binding affinity over ADP-ribose for SARS-CoV-2, MERS-CoV, VEEV, and CHIKV macrodomains. Moreover, building on these potent binders, we have developed two highly sensitive fluorescence polarization tracers that only require nanomolar proteins and can effectively resolve the binding affinities of nanomolar inhibitors. Our findings and probes described here will facilitate future development of more potent viral macrodomain inhibitors.

PubMed: 38646883
DOI: 10.1021/acschembio.4c00027

Experimental method

X-RAY DIFFRACTION (1.395 Å)