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

Content Provider	Royal Society of Chemistry (RSC)
Author	Smith, Anton A. A. Zuwala, Kaja Tolstrup, Martin Zelikin, Alexander N.
Copyright Year	2016
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.
Starting Page	2353
Ending Page	2358
Page Count	6
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	7
Issue Number	3
Journal	Chemical Science
DOI	10.1039/c5sc03257a
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Panobinostat Histone deacetylase Ester HIV Safety integrity level Disulfide Cytotoxicity Bioconjugation Prodrug Monomer
Content Type	Text
Resource Type	Article
Subject	Chemistry

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