New Molecular Targets and Strategies for Antimalarial Discovery

Author(s)

Aguiar, Anna Caroline ^[1] ; de Sousa, Lorena R. F. ^{[1, 2]} ; Garcia, Celia R. S. ^[3] ; Oliva, Glaucius ^[1] ; Guido, Rafael V. C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sao Carlos Inst Phys, POB 369, BR-13560970 Sao Carlos, SP - Brazil

^[2] Univ Fed Goias, Chem Dept, BR-75704020 Catalao, Go - Brazil

^[3] Univ Sao Paulo, Biosci Inst, Physiol Dept, Sao Paulo, SP - Brazil

• Document type: Review article
• Source: Current Medicinal Chemistry; v. 26, n. 23, p. 4380-4402, 2019.
• Web of Science Citations: 6

Abstract

Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable antimalarial drugs are desperately needed. New proteins have been investigated as molecular targets for research and development of innovative compounds with well-defined mechanism of action. In this review, we highlight genetically and clinically validated plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes described herein are involved in hemoglobin hydrolysis, the invasion process, elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications such as prenylation, phosphorylation and histone acetylation, generation of ATP in mitochondrial metabolism and aminoacylation of RNAs. Significant advances on proteomics, genetics, structural biology, computational and biophysical methods provided invaluable molecular and structural information about these drug targets. Based on this, several strategies and models have been applied to identify and improve lead compounds. This review presents the recent progresses in the discovery of antimalarial drug candidates, highlighting the approaches, challenges, and perspectives to deliver affordable, safe and low single-dose medicines to treat malaria. (AU)

• FAPESP's process: 11/51295-5 - Functional genomics in Plasmodium
• Grantee: Célia Regina da Silva Garcia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC