Antiplasmodial drug targets: a patent review (2000 – 2013)

Abstract

Introduction: New antimalarials with novel modes of action are crucial in countering the challenge of emerging drug-resistant Plasmodium falciparum. Equally significant is the identification and characterization of the targets these compounds inhibit. Biochemical evidence from seminal studies, whole genome clues and high-throughput chemical screening data provide starting points worth exploring in target identification efforts. Several proteins and biochemical processes/pathways critical to parasite survival have since been profiled and patented.

Areas covered: In this review, an analysis of patents describing the characterization of different enzymatic and/or biosynthetic targets in P. falciparum over the last fourteen years is presented. The review also details structures, biological evaluation, potential modes of action and therapeutic utilities of small molecule antiplasmodial compounds from ongoing research, designed to inhibit these targets.

Expert opinion: Though various strategies to address antimalarial drug resistance exist, direct inhibition of unrelated targets and non-genome coded processes potentially present the most effective options. Additionally, interest in peptides as antimalarials merits further exploration especially in view of their unique low susceptibility to resistance, wider spectrum of action and faster activity. Finally, target-based optimization and chemical validation of novel targets can be facilitated by routine phenotypic whole-cell screening of antiplasmodial hits against any new target(s).

Keywords:

• antimalarial peptides
• antimalarials
• malaria
• multiple target inhibition
• non-genome coded targets
• patent
• phenotypic whole cell screening
• Plasmodium falciparum
• target identification

Article highlights

• Biochemical profile results from seminal research, sequence clues from P. falciparum genome on essential proteins/processes and phenotypic data from high-throughput chemical screening have provided instructive guides, which have contributed to better understanding of inhibitor-target interactions in the parasite.

• Patents describing the identification and validation of ‘druggable’ antimalarial targets have been filed globally underscoring the immense interest in successful control of malaria through chemotherapy.

• Particular cellular processes like fatty acid synthesis are distinct in P. falciparum (type II instead of type I) while certain enzymes like the cGMP-dependent protein kinases are clearly differentiated from their mammalian orthologs, hence present attractive targets with minimal or no cytotoxic compromise to the human host.

• Multi-target and multi-stage inhibitions, targeting of process outside genomic control and optimizing peptides for use against P. falciparum stand out as effective approaches particularly in efforts to circumvent the development of antimalarial drug resistance. In fact, various compounds have already been reported with multi-target properties, while potent antimalarial peptides and inhibitors of non-genome coded targets also exist.

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