Novel epidithiodiketopiperazines as anti-viral zinc ejectors of the Feline Immunodeficiency Virus (FIV) nucleocapsid protein as a model for HIV infection

Christopher R M Asquith; Bruno C Sil; Tuomo Laitinen; Graham J Tizzard; Simon J Coles; Antti Poso; Regina Hofmann-Lehmann; Stephen T Hilton

doi:10.1016/j.bmc.2019.07.047

Novel epidithiodiketopiperazines as anti-viral zinc ejectors of the Feline Immunodeficiency Virus (FIV) nucleocapsid protein as a model for HIV infection

Bioorg Med Chem. 2019 Sep 15;27(18):4174-4184. doi: 10.1016/j.bmc.2019.07.047. Epub 2019 Jul 30.

Authors

Christopher R M Asquith¹, Bruno C Sil², Tuomo Laitinen³, Graham J Tizzard⁴, Simon J Coles⁴, Antti Poso³, Regina Hofmann-Lehmann⁵, Stephen T Hilton⁶

Affiliations

¹ School of Pharmacy, Faculty of Life Sciences, University College London, London WC1N 1AX, United Kingdom; Clinical Laboratory & Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: chris.asquith@unc.edu.
² School of Pharmacy, Faculty of Life Sciences, University College London, London WC1N 1AX, United Kingdom; School of Human Sciences, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, United Kingdom.
³ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland.
⁴ UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield Campus, Southampton SO17 1BJ, United Kingdom.
⁵ Clinical Laboratory & Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
⁶ School of Pharmacy, Faculty of Life Sciences, University College London, London WC1N 1AX, United Kingdom. Electronic address: s.hilton@ucl.ac.uk.

PMID: 31395510
DOI: 10.1016/j.bmc.2019.07.047

Abstract

Focused libraries of multi-substituted epidithiodiketopiperazines (ETP) were prepared and evaluated for efficacy of inhibiting the nucleocapsid protein function of the Feline Immunodeficiency Virus (FIV) as a model for HIV. This activity was compared and contrasted to observed toxicity utilising an in-vitro cell culture approach. This resulted in the identification of several promising lead compounds with nanomolar potency in cells with low toxicity and a favorable therapeutic index.

Keywords: Epidithiodiketopiperazines (ETP); Feline Immunodeficiency Virus (FIV); Human Immunodeficiency Virus (HIV); Nucleocapsid protein (NCp); Zinc ejection.

Publication types

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

MeSH terms

Animals
Cats
Disease Models, Animal
HIV Infections / drug therapy*
Humans
Immunodeficiency Virus, Feline / pathogenicity*
Nucleocapsid Proteins / metabolism*
Piperazines / pharmacology
Piperazines / therapeutic use*

Substances

Nucleocapsid Proteins
Piperazines