Muddled mechanisms: recent progress towards antimalarial target identification

Edwards, Rachel L.; John, Audrey Odom

doi:10.12688/f1000research.9477.1

Cited by 6 publications

(3 citation statements)

References 116 publications

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“…Drugs with improved efficacy and potency were introduced to deal with the resistance. Recent study on drug resistance showed that de novo resistances are appearing more rapidly [12,13]. The first case of drug resistance ever reported was in 1980, it was against Quinine [14].…”

Section: Treatment Regimesmentioning

confidence: 99%

Plasmodium falciparum: Experimental and Theoretical Approaches in Last 20 Years

Das¹,

Pathak²,

Rajkhowa³

et al. 2021

Current Topics and Emerging Issues in Malaria Elimination

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Malaria, the severe vector-borne disease has embedded serious consequences on mankind since ages, causing deterioration of health, leading to deaths. The causative parasite has a wide distribution aligned from tropical to subtropical regions. Out of all the five species Plasmodium vivax and Plasmodium falciparum have registered about more than 600 million cases worldwide. Throughout the decades, identification of various antimalarial drugs, targets, preventive measures and advancement of vaccines were achieved. The key to executing malaria elimination is the appropriate laboratory diagnosis. Development includes positive scientific judgments for a vaccine, advanced progress of 3 non-pyrethroid insecticides, novel genetic technologies, possibilities to alter malaria parasite mediation by the mosquito, identification of drug resistance markers, initiation of Plasmodium vivax liver stage assessment, perspective to mathematical modeling and screening for active ingredients for drugs and insecticides. Although the last century witnessed many successful programs with scientific progress, however, this was matched with notable obstacles. The mutation in the genes has changed the overall gameplay of eradication. This chapter aims to examine the numerous experimental and theoretical works that have been established in the last two decades along with the ongoing methodologies consisting of detailed explanations necessary for the establishment of new targets and drugs.

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Section: Treatment Regimesmentioning

confidence: 99%

Plasmodium falciparum: Experimental and Theoretical Approaches in Last 20 Years

Das¹,

Pathak²,

Rajkhowa³

et al. 2021

Current Topics and Emerging Issues in Malaria Elimination

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“…Namely, identifying the direct target(s) of an inhibitor provides the molecular basis for optimizing structure‐activity relationships and can also unveil novel druggable targets that in turn aid in target‐based drug discovery. Complicating drug‐target discovery efforts has been the increasing appreciation that many drugs, including antimalarial inhibitors, deliver their therapeutic effects by targeting multiple proteins [9–11] . This suggests that comprehensive profiling of drug targets is necessary to elucidate complicated mechanisms of drug action and prioritize compounds for further drug development.…”

Section: Introductionmentioning

confidence: 99%

Chemoproteomics for Plasmodium Parasite Drug Target Discovery

Mansfield

Fitzgerald

et al. 2021

ChemBioChem

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Emerging Plasmodium parasite drug resistance is threatening progress towards malaria control and elimination. While recent efforts in cell‐based, high‐throughput drug screening have produced first‐in‐class drugs with promising activities against different Plasmodium life cycle stages, most of these antimalarial agents have elusive mechanisms of action. Though challenging to address, target identification can provide valuable information to facilitate lead optimization and preclinical drug prioritization. Recently, proteome‐wide methods for direct assessment of drug‐protein interactions have emerged as powerful tools in a number of systems, including Plasmodium. In this review, we will discuss current chemoproteomic strategies that have been adapted to antimalarial drug target discovery, including affinity‐ and activity‐based protein profiling and the energetics‐based techniques thermal proteome profiling and stability of proteins from rates of oxidation. The successful application of chemoproteomics to the Plasmodium blood stage highlights the potential of these methods to link inhibitors to their molecular targets in more elusive Plasmodium life stages and intracellular pathogens in the future.

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“…In parallel, antimalarial drugs have been instrumental in preventing the most aggressive and lethal forms of the disease caused by Plasmodium falciparum . However, due to the limited structural diversity within the chemical scaffolds of current clinically-available drugs and the increased incidence of drug resistance, new antimalarial compounds with novel modes of action must be identified 2 – 4 .…”

Section: Introductionmentioning

confidence: 99%

Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin

Saraiva

Huitt-Roehl

Tripathi

et al. 2018

Sci Rep

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The Chromobacterium sp. Panama bacterium has in vivo and in vitro anti-Plasmodium properties. To assess the nature of the Chromobacterium-produced anti-Plasmodium factors, chemical partition was conducted by bioassay-guided fractionation where different fractions were assayed for activity against asexual stages of P. falciparum. The isolated compounds were further partitioned by reversed-phase FPLC followed by size-exclusion chromatography; high resolution UPLC and ESI/MS data were then collected and revealed that the most active fraction contained a cyclic depsipeptide, which was identified as romidepsin. A pure sample of this FDA-approved HDAC inhibitor allowed us to independently verify this finding, and establish that romidepsin also has potent effect against mosquito stages of the parasite’s life cycle. Genomic comparisons between C. sp. Panama and multiple species within the Chromobacterium genus further demonstrated a correlation between presence of the gene cluster responsible for romidepsin production and effective antiplasmodial activity. A romidepsin-null Chromobacterium spp. mutant loses its anti-Plasmodium properties by losing the ability to inhibit P. falciparum HDAC activity, and romidepsin is active against resistant parasites to commonly deployed antimalarials. This independent mode of action substantiates exploring a chromobacteria-based approach for malaria transmission-blocking.

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Muddled mechanisms: recent progress towards antimalarial target identification

Cited by 6 publications

References 116 publications

Plasmodium falciparum: Experimental and Theoretical Approaches in Last 20 Years

Plasmodium falciparum: Experimental and Theoretical Approaches in Last 20 Years

Chemoproteomics for Plasmodium Parasite Drug Target Discovery

Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin

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