Targeting intramolecular proteinase NS2B/3 cleavages for trans -dominant inhibition of dengue virus

Proceedings of the National Academy of Sciences of the United States of America
David A ConstantKarla Kirkegaard

Abstract

Many positive-strand RNA viruses translate their genomes as single polyproteins that are processed by host and viral proteinases to generate all viral protein products. Among these is dengue virus, which encodes the serine proteinase NS2B/3 responsible for seven different cleavages in the polyprotein. NS2B/3 has been the subject of many directed screens to find chemical inhibitors, of which the compound ARDP0006 is among the most effective at inhibiting viral growth. We show that at least three cleavages in the dengue polyprotein are exclusively intramolecular. By definition, such a cis-acting defect cannot be rescued in trans This creates the possibility that a drug-susceptible or inhibited proteinase can be genetically dominant, inhibiting the outgrowth of drug-resistant virus via precursor accumulation. Indeed, an NS3-G459L variant that is incapable of cleavage at the internal NS3 junction dominantly inhibited negative-strand RNA synthesis of wild-type virus present in the same cell. This internal NS3 cleavage site is the junction most inhibited by ARDP0006, making it likely that the accumulation of toxic precursors, not inhibition of proteolytic activity per se, explains the antiviral efficacy of this compound in restrainin...Continue Reading

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Citations

May 18, 2020·Journal of Medical Virology·Chaitanya GandikotaMusturi Venkataramana
Feb 18, 2020·Science Advances·Samuel T JonesCaroline Tapparel
Jun 26, 2020·Journal of Virology·Chaitanya GandikotaMusturi Venkataramana
Oct 30, 2020·Phytotherapy Research : PTR·Faraat AliAsad Ali
Nov 17, 2020·Frontiers in Pharmacology·Xiangling CuiShan Cen
Jul 24, 2021·European Journal of Medicinal Chemistry·Crystall SwarbrickGerasimos Rassias

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Methods Mentioned

BETA
X-ray
transfections
Assay
transfection
PCR

Software Mentioned

Clustal Omega
Lasergene MegAlign Pro
ImageQuant TL
GraphPad Prism

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