Novel Rational Drug Design Strategies with Potential to Revolutionize Malaria Chemotherapy

F.      W. Muregi; P.      G. Kirira; A.      Ishih

doi:10.2174/092986711793979742

Abstract

Efforts to develop an effective malaria vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to most antimalarial drugs in clinical use. This dire situation is aggravated by reports from Southeast Asia, of the parasite becoming resistant to the “magic bullet” artemisinins, the last line of defense in malaria chemotherapy. Drug development is a laborious and time consuming process, and thus antimalarial drug discovery approaches currently being deployed largely include optimization of therapy with available drugs — including combination therapy and developing analogues of the existing drugs. However, the latter strategy may be hampered by cross-resistance, since agents that are closely related chemically may share similar mechanisms of action and/or targets. This may render new drugs ineffective even before they are brought to clinical use. Evaluation of drug-resistance reversers (chemosensitizers) against quinoline-based drugs such as chloroquine and mefloquine is another approach that is being explored. Recently, evaluation of new chemotherapeutic targets is gaining new impetus as knowledge of malaria parasite biology expands. Also, single but hybrid molecules with dual functionality and/or targets have been developed through rational drug design approach, termed as “covalent bitherapy”. Since desperate times call for radical measures, this review aims to explore novel rational drug-design strategies potentially capable of revolutionizing malaria therapy. We thus explore malaria apoptosis machinery as a novel drug target, and also discuss the potential of hybrid molecules as well as prodrugs and double prodrugs in malaria chemotherapy.

Keywords: Antimalarial drugs, apoptosis, hybrid drugs, Plasmodium falciparum, prodrugs, topoisomerases, Rational Drug, Chemotherapy, protozoal parasite, Plasmodium, malaria, chloroquine, antifolates, World Health Organization, artesunate-sulfadoxine pyrimethamine, chemosensitizers, bioinformatics tools, cysteine, aspartic proteases, haemoglobin metabolism, intraerythrocytic, plasmepsins, peptidomimetic compounds, Protease inhibitors, purine salvage, pyrimidine biosynthetic, dehydrogenase, eukaryotes, neurological disorders, carboxy terminal, RNA polymerase II, plasmodial CDK inhibitors, Glutathione, Apicoplast, cytosol, fungi, Triclosan, haemoglobin, trophozoite, ciprofloxacin, schizogony, DNA, prosthetic groups, isoforms, lipoic acid, Depolarization, mitochondrial membrane, cytochrome, covalent bitherapy, anticancer agents, homeostatic functions, dysfunctional DNA, cell-shrinkage, necrosis, Entamoeba histolytica, Dictyostelium discoideum, intracellular K+, sodium nitroprusside, mitochondrial dysfunction, isolates, cytoplasmatic vacuolization, synchrony, cell shrinkage, Mosquitoes, vertebrate host, zygote, ookinete, sporogonic stage, density, orthologues, immune system, membrane blebbing, novel drug, calcium pools, transferrin receptor (TfR), intraerythrocytic parasites, promyelocytic leukemia, Reduction, cell-signaling enzymes, ADP-ribosylation, DNA Topoisomerases, supecoils, ATP, cofactor, padophyllotoxin, Epipodophyllotoxins, sarcoma, testicular cancer, acute lymphocytic leukemia, small-cell lung cancer, Inhibitors, anthracycline, poisons, hybrid molecules, xenobiotic detoxification, vasodilators, penfluridol, archaebacterial topoisomerase, alkylating agent, heterocycle, conjugated, drug's availability, verapamil, antiplasmodial activity, rational drug design, typical dual drug, elucidation of drugs, bioactive drug, Novel Rational Drug Design Strategies with Potential to Revolutionize Malaria Chemotherapy