
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.23.609196
preprint
1
Article
Identifying novel chemical matter against the Chikungunya virus nsP3 macrodomain through crystallographic fragment screening
Aschenbrenner Jasmin C. http://orcid.org/0000-0002-4318-0481

de Godoy Andre Schutzer http://orcid.org/0000-0002-0613-9164

Fairhead Michael http://orcid.org/0000-0001-5361-3933

Tomlinson Charles W.E. http://orcid.org/0000-0002-1845-6028

Winokan Max http://orcid.org/0000-0002-1318-4422

Balcomb Blake H. http://orcid.org/0000-0001-7599-8467

Capkin Eda http://orcid.org/0000-0003-4570-6683

Chandran Anu V. http://orcid.org/0000-0001-9942-2614

Golding Mathew http://orcid.org/0009-0004-7472-8333

Koekemoer Lizbe http://orcid.org/0000-0001-9226-9127

Lithgo Ryan M. http://orcid.org/0000-0002-4706-9916

Marples Peter G. http://orcid.org/0000-0002-8787-7969

Ni Xiaomin http://orcid.org/0000-0002-7769-8297

Thompson Warren http://orcid.org/0000-0003-1474-7810

Wild Conor http://orcid.org/0000-0003-0654-8141

Xavier Mary-Ann E. http://orcid.org/0000-0001-9672-0763

Fearon Daren http://orcid.org/0000-0003-3529-7863

von Delft Frank http://orcid.org/0000-0003-0378-0017

23 8 2024
2024.08.23.609196https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.23.609196
nihpp-2024.08.23.609196.pdf
Abstract

Chikungunya virus (CHIKV) causes severe fever, rash and debilitating joint pain that can last for months 1,2 or even years. Millions of people have been infected with CHIKV, mostly in low and middle-income countries, and the virus continues to spread into new areas due to the geographical expansion of its mosquito hosts. Its genome encodes a macrodomain, which functions as an ADP-ribosyl hydrolase, removing ADPr from viral and host-cell proteins interfering with the innate immune response. Mutational studies have shown that the CHIKV nsP3 macrodomain is necessary for viral replication, making it a potential target for the development of antiviral therapeutics. We, therefore, performed a high-throughput crystallographic fragment screen against the CHIKV nsP3 macrodomain, yielding 109 fragment hits covering the ADPr-binding site and two adjacent subsites that are absent in the homologous macrodomain of SARS-CoV-2 but may be present in other alphaviruses, such as Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV). Finally, a subset of overlapping fragments was used to manually design three fragment merges covering the adenine and oxyanion subsites. The rich dataset of chemical matter and structural information discovered from this fragment screen is publicly available and can be used as a starting point for developing a CHIKV nsP3 macrodomain inhibitor.
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