TY - JOUR
T1 - Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design
AU - Zhang, Sixue
AU - Garzan, Atefeh
AU - Haese, Nicole
AU - Bostwick, Robert
AU - Martinez-Gzegozewska, Yohanka
AU - Rasmussen, Lynn
AU - Streblow, Daniel N.
AU - Haise, Mark T.
AU - Pathak, Ashish K.
AU - Augelli-Szafran, Corinne E.
AU - Wu, Mousheng
N1 - Publisher Copyright:
© 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/1
Y1 - 2021/1
N2 - The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence. No small molecule drugs targeting CHIKV nsP3 have been identified to date. Here we report small fragments that bind to nsP3MD which were discovered by virtually screening a fragment library and X-ray crystallography. These identified fragments share a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Among the fragments, 2-oxo-5,6-benzopyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC50 of 23 ìM. Our fragment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4-carboxylic acid scaffold. In silico studies suggest this pyrimidone scaffold could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential panantiviral activity.
AB - The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence. No small molecule drugs targeting CHIKV nsP3 have been identified to date. Here we report small fragments that bind to nsP3MD which were discovered by virtually screening a fragment library and X-ray crystallography. These identified fragments share a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Among the fragments, 2-oxo-5,6-benzopyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC50 of 23 ìM. Our fragment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4-carboxylic acid scaffold. In silico studies suggest this pyrimidone scaffold could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential panantiviral activity.
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U2 - 10.1371/journal.pone.0245013
DO - 10.1371/journal.pone.0245013
M3 - Article
C2 - 33482665
AN - SCOPUS:85100308854
SN - 1932-6203
VL - 16
JO - PloS one
JF - PloS one
IS - 1 January
M1 - e0245013
ER -