Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2015 Jan 27

PMID 25619934

Citations 20

Authors

Magnus Joakim Hansson

Steven James Moss

Michael Bobardt

Udayan Chatterji

Nigel Coates

Jose A Garcia-Rivera

Eskil Elmer

Steve Kendrew

Pieter Leyssen

Johan Neyts

Mohammad Nur-E-Alam

Tony Warneck

Barrie Wilkinson

Philippe Gallay

Matthew Alan Gregory

Affiliations

Soon will be listed here.

Abstract

Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.

Citing Articles

Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV.

Newton L, Gathmann C, Ridewood S, Smith R, Wijaya A, Hornsby T Nat Commun. 2025; 16(1):1484.

PMID: 39929804 PMC: 11811207. DOI: 10.1038/s41467-025-56317-8.

Exploration of the Role of Cyclophilins in Established Hepatitis B and C Infections.

Molle J, Duponchel S, Rieusset J, Ovize M, Ivanov A, Zoulim F Viruses. 2025; 17(1.

PMID: 39861799 PMC: 11768883. DOI: 10.3390/v17010011.

Cyclophilin inhibition as a strategy for the treatment of human disease.

Stauffer W, Goodman A, Gallay P Front Pharmacol. 2024; 15:1417945.

PMID: 39045055 PMC: 11264201. DOI: 10.3389/fphar.2024.1417945.

Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH.

Stauffer W, Bobardt M, Ure D, Foster R, Gallay P PLoS One. 2024; 19(4):e0301711.

PMID: 38573968 PMC: 10994289. DOI: 10.1371/journal.pone.0301711.

The Cyclophilin Inhibitor Rencofilstat Decreases HCV-Induced Hepatocellular Carcinoma Independently of Its Antiviral Activity.

Stauffer W, Bobardt M, Ure D, Foster R, Gallay P Viruses. 2023; 15(10).

PMID: 37896876 PMC: 10612079. DOI: 10.3390/v15102099.

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