Molecular dissection of an inhibitor targeting the HIV integrase dependent preintegration complex nuclear import.

Cellular Microbiology
Kylie M WagstaffD A Jans

Abstract

Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new antiviral agents against novel targets are still urgently required. We previously identified novel anti-HIV agents directed against the nuclear import of the HIV integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV preintegration complex (PIC) into the nucleus. Here we investigate the structure activity relationship of a series of these compounds for the first time, including a newly identified anti-IN compound, budesonide, showing that the extent of binding to the IN core domain correlates directly with the ability of the compound to inhibit IN nuclear transport in a permeabilised cell system. Importantly, compounds that inhibited the nuclear transport of IN were found to significantly decrease HIV viral replication, even in a dividing cell system. Significantly, budesonide or its analogue flunisolide, were able to effect a significant reduction ...Continue Reading

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Citations

Aug 31, 2019·The Journal of Biological Chemistry·Alan N Engelman
Sep 19, 2020·Cells·David A Jans, Kylie M Wagstaff
Nov 12, 2020·Nature Reviews. Drug Discovery·Giampaolo CalissiWolfgang Link
Dec 10, 2020·The FEBS Journal·Chih-Chia Chang, Kuo-Chiang Hsia
Dec 19, 2020·Nucleic Acids Research·Gregory J Bedwell, Alan N Engelman
Jan 14, 2021·Biochemical Society Transactions·Alexander J Martin, David A Jans
Jun 3, 2021·Viruses·Maryam TabasiZeger Debyser

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR
AlphaScreen
light microscopy
PCR
dissection
transfection

Software Mentioned

ImageJ
Graphpad Prism
AlphaScreen

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