Microsporidiosis: Rational Therapeutics

Project: Research project

Project Details

Description

The Microsporidia are emerging zoonotic pathogenic protists which are classified as
category B priorty pathogens by the NIH and are also on the EPA high priority organism
and contaminant lists. New drugs are needed, both for topical treatment of ocular
microsporidiosis as well as systemic treatment of disseminated and gastrointestinal
infections. This application represents an approach to rational drug design for these
difficult pathogens. Our data, and that of other groups, indicates that fumagillin functions
by inhibiting microsporidian methionine aminopeptidase type 2 (MetAP2) which is an
essential enzyme in these organisms. We have cloned, expressed and determined the
crystal structure of Encephalitozoon cuniculi MetAP2 (EcMetAP2) as well as developed
yeast dependent on EcMetAP2 for growth. In addition, we have identified and cloned
Enterocytozoon bieneusi MetAP2 (EbMetAP2). MetAP2 is a logical therapeutic target as
microsporidia lack MetAP1 making MetAP2 an essential enzyme. Among eukaryotes
this makes them highly susceptible to MetAP2 inhibitors and limits the toxicity of these
compounds in their hosts as most eukaryotes have both MetAP1 and MetAP2. Use of
fumagillin and its derivatives has confirmed that inhibition of MetAP2 is an effective in
vitro and in vivo therapeutic target for many species of microsporidia suggesting that like
E. cuniculi other microsporidia are dependent on MetAP2. Fumagillin has demonstrated
efficacy in human infections due to Ent. bieneusi, but its use has been limited by bone
marrow toxicity. Exploiting differences in the structure of MetAP2 between host and
pathogen should permit the design of selective therapeutic competitive agents with
decreased host toxicity. We plan to develop new competivie inhibitors of MetAP2 with
increased selectivity for microsporidia, based on our EcMetAP2 crystal structure and in
silico model of EbMetAP2. These inhibitors will be tested in vitro and in vivo for efficacy
and in an iterative process we will use this information to refine our models and improve
inhibitor design. We have assembled an integrated team with complementary expertise
to develop and test these compounds. In addition, the target enzyme MetAP2 is
important in other protozoa and our lead compounds should help define new classes of
drugs that could have broad anti-parasitic activity and prove useful in the treatment of
malaria and leishmaniasis.
StatusFinished
Effective start/end date9/1/118/31/13

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)
  • Infectious Diseases