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Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling.

Lim SP, Noble CG, Seh CC, Soh TS, El Sahili A, Chan GK, Lescar J, Arora R, Benson T, Nilar S, Manjunatha U, Wan KF, Dong H, Xie X, Shi PY, Yokokawa F
PLoS Pathog 12 e1005737 (2016)
Related entries: 5i3p, 5i3q, 5jjr, 5k5m

Cited: 67 times
EuropePMC logo PMID: 27500641

Abstract

Flaviviruses comprise major emerging pathogens such as dengue virus (DENV) or Zika virus (ZIKV). The flavivirus RNA genome is replicated by the RNA-dependent-RNA polymerase (RdRp) domain of non-structural protein 5 (NS5). This essential enzymatic activity renders the RdRp attractive for antiviral therapy. NS5 synthesizes viral RNA via a "de novo" initiation mechanism. Crystal structures of the flavivirus RdRp revealed a "closed" conformation reminiscent of a pre-initiation state, with a well ordered priming loop that extrudes from the thumb subdomain into the dsRNA exit tunnel, close to the "GDD" active site. To-date, no allosteric pockets have been identified for the RdRp, and compound screening campaigns did not yield suitable drug candidates. Using fragment-based screening via X-ray crystallography, we found a fragment that bound to a pocket of the apo-DENV RdRp close to its active site (termed "N pocket"). Structure-guided improvements yielded DENV pan-serotype inhibitors of the RdRp de novo initiation activity with nano-molar potency that also impeded elongation activity at micro-molar concentrations. Inhibitors exhibited mixed inhibition kinetics with respect to competition with the RNA or GTP substrate. The best compounds have EC50 values of 1-2 μM against all four DENV serotypes in cell culture assays. Genome-sequencing of compound-resistant DENV replicons, identified amino acid changes that mapped to the N pocket. Since inhibitors bind at the thumb/palm interface of the RdRp, this class of compounds is proposed to hinder RdRp conformational changes during its transition from initiation to elongation. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors. Given the evolutionary conservation of residues lining the N pocket, these molecules offer insights to treat other serious conditions caused by flaviviruses.

Reviews - 5jjs mentioned but not cited (1)

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Articles - 5jjs mentioned but not cited (7)

  1. Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling. Lim SP, Noble CG, Seh CC, Soh TS, El Sahili A, Chan GK, Lescar J, Arora R, Benson T, Nilar S, Manjunatha U, Wan KF, Dong H, Xie X, Shi PY, Yokokawa F. PLoS Pathog 12 e1005737 (2016)
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Reviews citing this publication (18)

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