Affiliation:
1. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, K7L 3N6, Canada
2. Department of Chemistry, Queen's University, Kingston, ON, K7L 3N6, Canada
Abstract
The development of isozyme-selective heme oxygenase (HO) inhibitors promises
powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It
is already known that HO has cytoprotective properties with a role in several disease states;
thus, it is an enticing therapeutic target. Historically, the metalloporphyrins have been used as
competitive HO inhibitors based on their structural similarity to the substrate, heme. However,
heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase),
results in non-selectivity being an unfortunate side effect. Reports that azalanstat and
other non-porphyrin molecules inhibited HO led to a multi-faceted effort over a decade ago to
develop novel compounds as potent, selective inhibitors of HO. The result was the creation of
the first generation of non-porphyrin based, non-competitive inhibitors with selectivity for
HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the
structures of several complexes of HO-1 with novel inhibitors have been elucidated and provided
insightful information regarding the salient features required for inhibitor binding. This
included the structural basis for non-competitive inhibition, flexibility and adaptability of the
inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited
in future drug-design strategies. Notably, HO-1 inhibitors are of particular interest for
the treatment of hyperbilirubinemia and certain types of cancer. Key features based on this
initial study have already been used by others to discover additional potential HO-1 inhibitors.
Moreover, studies have begun to use selected compounds and determine their effects in some
disease models.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry
Cited by
7 articles.
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