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Two RNA Tunnel Inhibitors Bind in Highly Conserved Sites in Dengue Virus NS5 Polymerase: Structural and Functional Studies.

Arora R, Liew CW, Soh TS, Otoo DA, Seh CC, Yue K, Nilar S, Wang G, Yokokawa F, Noble CG, Chen YL, Shi PY, Lescar J, Smith TM, Benson TE, Lim SP
J Virol 94 (2020)
Cited: 7 times
EuropePMC logo PMID: 32907977

Abstract

Dengue virus (DENV) NS5 RNA-dependent RNA polymerase (RdRp), an important drug target, synthesizes viral RNA and is essential for viral replication. While a number of allosteric inhibitors have been reported for hepatitis C virus RdRp, few have been described for DENV RdRp. Following a diverse compound screening campaign and a rigorous hit-to-lead flowchart combining biochemical and biophysical approaches, two DENV RdRp nonnucleoside inhibitors were identified and characterized. These inhibitors show low- to high-micromolar inhibition in DENV RNA polymerization and cell-based assays. X-ray crystallography reveals that they bind in the enzyme RNA template tunnel. One compound (NITD-434) induced an allosteric pocket at the junction of the fingers and palm subdomains by displacing residue V603 in motif B. Binding of another compound (NITD-640) ordered the fingers loop preceding the F motif, close to the RNA template entrance. Most of the amino acid residues that interacted with these compounds are highly conserved in flaviviruses. Both sites are important for polymerase de novo initiation and elongation activities and essential for viral replication. This work provides evidence that the RNA tunnel in DENV RdRp offers interesting target sites for inhibition.

Reviews - 6xd1 mentioned but not cited (1)

  1. Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies. Ramaswamy K, Rashid M, Ramasamy S, Jayavelu T, Venkataraman S. Viruses 14 2200 (2022)

Articles - 6xd1 mentioned but not cited (1)

  1. Two RNA Tunnel Inhibitors Bind in Highly Conserved Sites in Dengue Virus NS5 Polymerase: Structural and Functional Studies. Arora R, Liew CW, Soh TS, Otoo DA, Seh CC, Yue K, Nilar S, Wang G, Yokokawa F, Noble CG, Chen YL, Shi PY, Lescar J, Smith TM, Benson TE, Lim SP. J Virol 94 e01130-20 (2020)


Reviews citing this publication (2)

  1. Virus structure and structure-based antivirals. Plavec Z, Pöhner I, Poso A, Butcher SJ. Curr Opin Virol 51 16-24 (2021)
  2. Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview. Diani E, Lagni A, Lotti V, Tonon E, Cecchetto R, Gibellini D. Microorganisms 11 2427 (2023)

Articles citing this publication (3)

  1. Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches. Ramos PRPDS, Mottin M, Lima CS, Assis LR, de Oliveira KZ, Mesquita NCMR, Cassani NM, Santos IA, Borba JVVB, Fiaia Costa VA, Neves BJ, Guido RVC, Oliva G, Jardim ACG, Regasini LO, Andrade CH. Pharmaceuticals (Basel) 15 1493 (2022)
  2. Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication. Boerneke MA, Gokhale NS, Horner SM, Weeks KM. Proc Natl Acad Sci U S A 120 e2217053120 (2023)
  3. The 8-bromobaicalein inhibited the replication of dengue, and Zika viruses and targeted the dengue polymerase. Boonyasuppayakorn S, Saelee T, Huynh TNT, Hairani R, Hengphasatporn K, Loeanurit N, Cao V, Vibulakhaophan V, Siripitakpong P, Kaur P, Chu JJH, Tunghirun C, Choksupmanee O, Chimnaronk S, Shigeta Y, Rungrotmongkol T, Chavasiri W. Sci Rep 13 4891 (2023)


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