Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that selectively "Freeze" the pre-translocated complex during the polymerization catalytic cycle

Cyrus M Lacbay; Michael Menni; Jean A Bernatchez; Matthias Götte; Youla S Tsantrizos

doi:10.1016/j.bmc.2018.02.017

Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that selectively "Freeze" the pre-translocated complex during the polymerization catalytic cycle

Bioorg Med Chem. 2018 May 1;26(8):1713-1726. doi: 10.1016/j.bmc.2018.02.017. Epub 2018 Feb 14.

Authors

Cyrus M Lacbay¹, Michael Menni², Jean A Bernatchez², Matthias Götte³, Youla S Tsantrizos⁴

Affiliations

¹ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
² Department of Biochemistry, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G1Y6, Canada.
³ Department of Medical Microbiology and Immunology, University of Alberta, 6-020 Katz Group Centre, Edmonton, Alberta T6G 2E1, Canada; Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada.
⁴ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada; Department of Biochemistry, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G1Y6, Canada. Electronic address: youla.tsantrizos@mcgill.ca.

PMID: 29478802
DOI: 10.1016/j.bmc.2018.02.017

Abstract

Reverse transcriptase (RT) is responsible for replicating the HIV-1 genome and is a validated therapeutic target for the treatment of HIV infections. During each cycle of the RT-catalyzed DNA polymerization process, inorganic pyrophosphate is released as the by-product of nucleotide incorporation. Small molecules were identified that act as bioisosteres of pyrophosphate and can selectively freeze the catalytic cycle of HIV-1 RT at the pre-translocated stage of the DNA- or RNA-template-primer-enzyme complex.

Keywords: HIV-1 RT; Pre-translocated complex; Pyrimidinol carboxylic acids; Pyrophosphate mimics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biocatalysis
DNA, Viral / drug effects
DNA, Viral / genetics
Diphosphates / chemical synthesis
Diphosphates / chemistry
Diphosphates / pharmacology*
Dose-Response Relationship, Drug
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / genetics
HIV Reverse Transcriptase / metabolism
Molecular Structure
Polymerization / drug effects
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

DNA, Viral
Diphosphates
Reverse Transcriptase Inhibitors
Small Molecule Libraries
diphosphoric acid
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase

Grants and funding

CIHR/Canada