Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16-53 nM), matched with a high potency against P. vivax field isolates (Mean IC50 29 nM). Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P.berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.
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PMID:In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial. 2919 47

Reaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of the parasite to a mosquito, by preventing formation or transmission of gametocytes. An alternative approach, pioneered in the veterinary field, is to use endectocides, which are molecules that render vertebrate blood meals toxic for the mosquito vector, also killing the parasite. Field studies and modelling suggest that reducing the lifespan of the mosquito may significantly reduce transmission, given the lengthy maturation process of the parasite. To guide the development of new endectocides, or the reformulation of existing molecules, it is important to construct a framework of the required attributes, commonly called the target candidate profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a regulatory strategy are proposed for a transmission reducing agent. The parameters chosen can be used to assess the potential of a new medicine, independent of whether it has classical endectocide activity, reduces the insect and parasite lifespan or any combination of all three, thereby constituting an 'endectocidal transmission blocking' paradigm.
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PMID:A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria. 3052 94

The antihistamine clemastine inhibits multiple stages of the Plasmodium parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of clemastine and identify that clemastine binds to the Plasmodium falciparum TCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight P. falciparum TRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a clemastine-induced thermodynamic stabilization of the Plasmodium TRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that clemastine reduces levels of the major TRiC substrate tubulin in P. falciparum parasites. In addition, clemastine treatment leads to disorientation of Plasmodium mitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species selectivity required for targeting an intracellular human pathogen. Our findings encourage larger efforts to apply chemoproteomic methods to assist in target identification of antimalarial drugs and highlight the potential to selectively target Plasmodium TRiC-mediated protein folding for malaria intervention.
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PMID:Plasmodium chaperonin TRiC/CCT identified as a target of the antihistamine clemastine using parallel chemoproteomic strategy. 3212 89

Prefoldin (PFD) is a heterohexameric molecular chaperone which bind unfolded proteins and subsequently deliver them to a group II chaperonin for correct folding. Although there is structural and functional information available for humans and archaea PFDs, their existence and functions in malaria parasite remains uncharacterized. In the present review, we have collected the available information on prefoldin family members of archaea and humans and attempted to analyze unexplored PFD subunits of Plasmodium falciparum (Pf). Our review enhances the understanding of probable functions, structure and mechanism of substrate binding of Pf prefoldin by comparing with the available information of its homologs in archaea and H. sapiens. Three PfPFD out of six and a Pf prefoldin-like protein are reported to be essential for parasite survival that signifies their importance in malaria parasite biology. Transcriptome analyses suggest that PfPFD subunits are up-regulated at the mRNA level during asexual and sexual stages of parasite life cycle. Our in silico analysis suggested several pivotal proteins like myosin E, cytoskeletal protein (tubulin), merozoite surface protein and ring exported protein 3 as their interacting partners. Based on structural information of archaeal and H. sapiens PFDs, P. falciparum counterparts have been modelled and key interface residues were identified that are critical for oligomerization of PfPFD subunits. We collated information on PFD-substrate binding and PFD-chaperonin interaction in detail to understand the mechanism of substrate delivery in archaea and humans. Overall, our review enables readers to view the PFD family comprehensively. Communicated by Ramaswamy H. Sarma Abbreviations: HSP: Heat shock proteins; CCT: Chaperonin containing TCP-1; PFD: Prefoldin; PFLP: Prefoldin like protein; PfPFD: Plasmodium falciparum prefoldin; Pf: Plasmodium falciparum; H. sapiens: Homo sapiens; M. thermoautotrophicus: Methanobacterium thermoautotrophicus; P. horikoshii: Pyrococcus horikoshii.
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PMID:Comparative structural insight into prefoldin subunints of archaea and eukaryotes with special emphasis on unexplored prefoldin of Plasmodium falciparum. 3327 34