Potent and selective inhibitors for M32 metallocarboxypeptidases identified from high-throughput screening of anti-kinetoplastid chemical boxes
Active M32 inhibitor structures
Abstract
In recent years, the pharmaceutical company GlaxoSmithKline announced the disclosure of small collections of antiparasitic compounds to facilitate research and drug development for three of the main Tropical Neglected Diseases- i.e. Human African Trypanosomiasis, Leishmaniasis and Chagas Disease. These collections include new chemical entities with potential novel mechanisms of action that are likely to be active against a wide variety of targets. Taking advantage of these open access molecules, we successfully set up medium-throughput screening assays to find the first inhibitors of two metallocarboxypeptidases of the M32 family, a group of proteolytic enzymes proposed to play several roles in the biology of trypanosomatids including peptide catabolism, maintenance of parasite adaptive fitness and hydrolysis of bioactive peptides from the human host.
Funding
PICTO-Glaxo-0067 Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), Argentina.
Lionel Urán Landaburu
Former Lab Member (2016 – 2023)
PhD Fellow, teacher and science divulgation enthusiast.
Fernán Agüero
Principal Investigator, Assistant Professor
Using and generating data to guide discovery of new drugs and diagnostics.