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Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design.

Zhang S, Garzan A, Haese N, Bostwick R, Martinez-Gzegozewska Y, Rasmussen L, Streblow DN, Haise MT, Pathak AK, Augelli-Szafran CE, Wu M
PLoS One 16 e0245013 (2021)
Related entries: 6vuq, 6w0t, 6w7h, 6w8k, 6w8m, 6w8q, 6w8y, 6w91

Cited: 12 times
EuropePMC logo PMID: 33482665

Abstract

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 μM. 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 pan-antiviral activity.

Articles - 6w8z mentioned but not cited (1)

  1. Imidazonaphthyridine effects on Chikungunya virus replication: Antiviral activity by dependent and independent of interferon type 1 pathways. Ruiz UEA, Santos IA, Grosche VR, Fernandes RS, de Godoy AS, Torres JDA, Freire MCLC, Mesquita NCMR, Guevara-Vega M, Nicolau-Junior N, Sabino-Silva R, Mineo TWP, Oliva G, Jardim ACG. Virus Res 324 199029 (2023)


Reviews citing this publication (3)

  1. Antivirals against the Chikungunya Virus. Battisti V, Urban E, Langer T. Viruses 13 1307 (2021)
  2. The life cycle of the alphaviruses: From an antiviral perspective. Skidmore AM, Bradfute SB. Antiviral Res 209 105476 (2023)
  3. A review on structural genomics approach applied for drug discovery against three vector-borne viral diseases: Dengue, Chikungunya and Zika. Sundar S, Piramanayagam S, Natarajan J. Virus Genes 58 151-171 (2022)

Articles citing this publication (8)

  1. The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses. Leung AKL, Griffin DE, Bosch J, Fehr AR. Pathogens 11 94 (2022)
  2. In silico analysis of SARS-CoV-2 proteins as targets for clinically available drugs. Chan WKB, Olson KM, Wotring JW, Sexton JZ, Carlson HA, Traynor JR. Sci Rep 12 5320 (2022)
  3. Macrodomain Binding Compound MRS 2578 Inhibits Alphavirus Replication. Mattila S, Merilahti P, Wazir S, Quirin T, Maksimainen MM, Zhang Y, Xhaard H, Lehtiö L, Ahola T. Antimicrob Agents Chemother 65 e0139821 (2021)
  4. Antiviral activity of myricetin glycosylated compounds isolated from Marcetia taxifolia against chikungunya virus. Muñoz AL, Cuéllar AF, Arévalo G, Santamaría BD, Rodríguez AK, Buendia-Atencio C, Reyes Chaparro A, Tenorio Barajas AY, Segura NA, Bello F, Suárez AI, Rangel HR, Losada-Barragán M. EXCLI J 22 716-731 (2023)
  5. Host Factor Nucleophosmin 1 (NPM1/B23) Exerts Antiviral Effects against Chikungunya Virus by Its Interaction with Viral Nonstructural Protein 3. Pradeep P, Sivakumar KC, Sreekumar E. Microbiol Spectr 11 e0537122 (2023)
  6. Identification of mosquito proteins that differentially interact with alphavirus nonstructural protein 3, a determinant of vector specificity. Byers NM, Burns PL, Stuchlik O, Reed MS, Ledermann JP, Pohl J, Powers AM. PLoS Negl Trop Dis 17 e0011028 (2023)
  7. The 8-bromobaicalein alleviated chikungunya-induced musculoskeletal inflammation and reduced the viral load in healthy adult mice. Cao V, Loeanurit N, Hengphasatporn K, Hairani R, Wacharachaisurapol N, Prompila N, Wittayalertpanya S, Shigeta Y, Khotavivattana T, Chavasiri W, Boonyasuppayakorn S. Emerg Microbes Infect 12 2270074 (2023)
  8. The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus. Puhl AC, Fernandes RS, Godoy AS, Gil LHVG, Oliva G, Ekins S. Bioorg Med Chem 83 117239 (2023)


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