Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?


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Abstract

Malaria is a devastating infectious disease that affects large swathes of human populations across the planet’s tropical regions. It is caused by parasites of the genus Plasmodium, with Plasmodium falciparum being responsible for the most lethal form of the disease. During the intraerythrocytic stage in the human hosts, malaria parasites multiply and degrade hemoglobin (Hb) using a battery of proteases, which include two cysteine proteases, falcipains 2 and 3 (FP-2 and FP-3). Due to their role as major hemoglobinases, FP-2 and FP-3 have been targeted in studies aiming to discover new antimalarials and numerous inhibitors with activity against these enzymes, and parasites in culture have been identified. Nonetheless, cross-inhibition of human cysteine cathepsins remains a serious hurdle to overcome for these compounds to be used clinically. In this article, we have reviewed key functional and structural properties of FP-2/3 and described different compound series reported as inhibitors of these proteases during decades of active research in the field. Special attention is also paid to the wide range of computer-aided drug design (CADD) techniques successfully applied to discover new active compounds. Finally, we provide guidelines that, in our understanding, will help advance the rational discovery of new FP-2/3 inhibitors.

About the authors

Jorge González

Multiuser Center for Biomolecular Innovation, IBILCE/UNESP,

Author for correspondence.
Email: info@benthamscience.net

Emir Salas-Sarduy

Instituto de Investigaciones Biotecnológicas Dr. Rodolfo Ugalde, Universidad Nacional de San Martín

Email: info@benthamscience.net

Lilian Alvarez

Multiuser Center for Biomolecular Innovation,, IBILCE/UNESP

Email: info@benthamscience.net

Pedro Valiente

Donnelly Centre for Cellular & Biomolecular Research, University of Toronto

Email: info@benthamscience.net

Raghuvir Arni

Multiuser Center for Biomolecular Innovation, I, IBILCE/UNESP

Email: info@benthamscience.net

Pedro Pascutti

Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro

Email: info@benthamscience.net

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