Ribonuclease H/DNA Polymerase HIV-1 Reverse Transcriptase Dual Inhibitor: Mechanistic Studies on the Allosteric Mode of Action of Isatin-Based Compound RMNC6

PloS One
Angela CoronaEnzo Tramontano

Abstract

The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being natur...Continue Reading

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Citations

Jan 4, 2017·Virus Research·Luis Menéndez-AriasMar Álvarez
Mar 4, 2017·European Journal of Medicinal Chemistry·Vijay P SonarFilippo Cottiglia
Oct 25, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Claudia MelisElias Maccioni
Oct 22, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Rita MeledduElias Maccioni
Oct 27, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Serena MassariOriana Tabarrini
Mar 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Angela CoronaEnzo Tramontano
Mar 11, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jenny DesantisOriana Tabarrini
Sep 25, 2019·Antiviral Research·Enzo TramontanoLuis Menéndez-Arias
May 22, 2020·ACS Medicinal Chemistry Letters·Pedro A Sánchez-MurciaMaría-José Camarasa
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rita MeledduElias Maccioni
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Francesca GuzzoBrigida D'Abrosca

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Methods Mentioned

BETA
ion exchange chromatography
Hi-trap
ionic exchange
thermal shift

Software Mentioned

OPLS
LightCycler 480
Jaguar
QMPL Suite
Qsiteversion6
Maestro
Glide
Sigmaplot10

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