The inhibition process of HIV-1 integrase by diketoacids molecules: Understanding the factors governing the better efficiency of dolutegravir

Léa El Khoury; Jean-Philip Piquemal; Serge Fermandjian; Richard G Maroun; Nohad Gresh; Zeina Hobaika

doi:10.1016/j.bbrc.2017.05.001

The inhibition process of HIV-1 integrase by diketoacids molecules: Understanding the factors governing the better efficiency of dolutegravir

Biochem Biophys Res Commun. 2017 Jul 1;488(3):433-438. doi: 10.1016/j.bbrc.2017.05.001. Epub 2017 May 3.

Authors

Léa El Khoury¹, Jean-Philip Piquemal², Serge Fermandjian³, Richard G Maroun⁴, Nohad Gresh⁵, Zeina Hobaika⁶

Affiliations

¹ UR EGP, Centre d'Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, B.P. 11-514 Riad El Solh, Beirut 1107 2050, Lebanon; Laboratoire de Chimie Théorique, UMR7616 CNRS, UPMC, Sorbonne Universités, Paris 75005, France. Electronic address: lea.khoury4@net.usj.edu.lb.
² Laboratoire de Chimie Théorique, UMR7616 CNRS, UPMC, Sorbonne Universités, Paris 75005, France; Institut Universitaire de France, Paris Cedex 05, 75231, France; Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, United States. Electronic address: jpp@lct.jussieu.fr.
³ Chemistry and Biology Nucleo(S)Tides and Immunology for Therapy (CBNIT), UMR 8601 CNRS, UFR Biomédicale, Paris, France. Electronic address: sfermandjian@gmail.com.
⁴ UR EGP, Centre d'Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, B.P. 11-514 Riad El Solh, Beirut 1107 2050, Lebanon. Electronic address: richard.maroun@usj.edu.lb.
⁵ Laboratoire de Chimie Théorique, UMR7616 CNRS, UPMC, Sorbonne Universités, Paris 75005, France. Electronic address: gresh@lct.jussieu.fr.
⁶ UR EGP, Centre d'Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, B.P. 11-514 Riad El Solh, Beirut 1107 2050, Lebanon. Electronic address: zeina.hobaika@usj.edu.lb.

PMID: 28478035
DOI: 10.1016/j.bbrc.2017.05.001

Abstract

The Human Immunodeficiency Virus-1 integrase is responsible for the covalent insertion of a newly synthesized double-stranded viral DNA into the host cells, and is an emerging target for antivirus drug design. Raltegravir (RAL) and elvitegravir (EVG) are the first two integrase strand transfer inhibitors used in therapy. However, treated patients eventually develop detrimental resistance mutations. By contrast, a recently approved drug, dolutegravir (DTG), presents a high barrier to resistance. This study aims to understand the increased efficiency of DTG upon focusing on its interaction properties with viral DNA. The results showed DTG to be involved in more extended interactions with viral DNA than EVG. Such interactions involve the halobenzene and scaffold of DTG and EVG and bases 5'G^-43', 3'A³5'and 3'C⁴5'.

Keywords: Dolutegravir; Elvitegravir; Human Immunodeficiency Virus-1; Integrase strand transfer inhibitors; Viral DNA.

MeSH terms

DNA, Viral / drug effects
Dose-Response Relationship, Drug
Fluorescence Polarization
HIV Integrase / metabolism*
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology*
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacology*
Keto Acids / chemistry
Keto Acids / pharmacology*
Models, Molecular
Molecular Conformation
Oxazines
Piperazines
Pyridones
Structure-Activity Relationship

Substances

DNA, Viral
HIV Integrase Inhibitors
Heterocyclic Compounds, 3-Ring
Keto Acids
Oxazines
Piperazines
Pyridones
dolutegravir
HIV Integrase
p31 integrase protein, Human immunodeficiency virus 1