Issue 3, 2016

HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat

Abstract

Histone deacetylase inhibitors (HDACi) and panobinostat in particular are currently in the focus of intensive investigation as latency reversing agents against the human immunodeficiency virus (HIV). Regretfully, HDACi have dose limiting side-effects making controlled, optimized methods for delivery of panobinostat highly warranted. This has proven to be highly challenging, predominantly because panobinostat has no readily available classic sites for bioconjugation. In this work, we address this challenge and present the first macromolecular prodrugs of panobinostat engineered using self immolative linkers (SIL) and a disulfide trigger for drug release upon cell entry. Synthetic methodology involved the development of a novel monomer with functionalities of SIL and activated ester for one-step polymer-analogous conjugation to drugs. In agreement with the design set forward, copolymers were stable in buffered solutions and released panobinostat at reducing conditions. Synthesized polymers were highly efficacious as latency reversing agents as monitored in three cell lines harboring latent HIV, at no expense to the cytotoxicity of treatment. The data presented herein provide broad pre-in vivo characterization of a promising prodrug system developed to address a global healthcare challenge, safe and efficient reversal of HIV latency.

Graphical abstract: HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat

Supplementary files

Article information

Article type
Edge Article
Submitted
31 Aug 2015
Accepted
26 Dec 2015
First published
05 Jan 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 2353-2358

Author version available

HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat

K. Zuwala, A. A. A. Smith, M. Tolstrup and A. N. Zelikin, Chem. Sci., 2016, 7, 2353 DOI: 10.1039/C5SC03257A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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