Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

Therese Ku; Natalie Lopresti; Matthew Shirley; Mattia Mori; Jan Marchant; Xiao Heng; Maurizio Botta; Michael F Summers; Katherine L Seley-Radtke

doi:10.1016/j.bmc.2019.05.019

Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

Bioorg Med Chem. 2019 Jul 1;27(13):2883-2892. doi: 10.1016/j.bmc.2019.05.019. Epub 2019 May 15.

Authors

Therese Ku¹, Natalie Lopresti¹, Matthew Shirley¹, Mattia Mori², Jan Marchant¹, Xiao Heng¹, Maurizio Botta³, Michael F Summers⁴, Katherine L Seley-Radtke⁵

Affiliations

¹ University of Maryland, Baltimore County, Department of Chemistry and Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
² University of Siena, Department of Biotechnology, Chemistry and Pharmacy, via Aldo Moro 2, 53100 Siena, Italy.
³ University of Siena, Department of Biotechnology, Chemistry and Pharmacy, via Aldo Moro 2, 53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA.
⁴ University of Maryland, Baltimore County, Department of Chemistry and Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA; Howard Hughes Medical Institute, USA.
⁵ University of Maryland, Baltimore County, Department of Chemistry and Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: kseley@umbc.edu.

Abstract

Anti-HIV-1 drug design has been notably challenging due to the virus' ability to mutate and develop immunity against commercially available drugs. The aims of this project were to develop a series of fleximer base analogues that not only possess inherent flexibility that can remain active when faced with binding site mutations, but also target a non-canonical, highly conserved target: the nucleocapsid protein of HIV (NC). The compounds were predicted by computational studies not to function via zinc ejection, which would endow them with significant advantages over non-specific and thus toxic zinc-ejectors. The target fleximer bases were synthesized using palladium-catalyzed cross-coupling techniques and subsequently tested against NC and HIV-1. The results of those studies are described herein.

Keywords: Fleximers; HIV-1; NC; Pyrimidine; Synthesis.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / chemistry*
HIV-1 / genetics*
Humans
Molecular Structure
Nucleocapsid Proteins / genetics*

Substances

Anti-HIV Agents
Nucleocapsid Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding