The problem of antimalarial resistance and its implications for drug discovery

Schäfer, Thomas Martin; Pessanha de Carvalho, Lais; Inoue, Juliana; Kreidenweiss, Andrea; Held, Jana

doi:10.1080/17460441.2023.2284820

Expert Opinion on Drug Discovery

2023

DOI: 10.1080/17460441.2023.2284820

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The problem of antimalarial resistance and its implications for drug discovery

Thomas Martin Schäfer,

Lais Pessanha de Carvalho,

Juliana Inoue

et al.

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2024

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Cited by 3 publications

(1 citation statement)

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“…Field surveillance measures that identify resistance to artemisinin derivatives and partner drugs to inform the adoption of different drug combinations are critical in the ongoing battle against drug resistance. − Rotational use of drug components in combination therapies is a promising strategy for managing resistance, , and antimalarial drug partners with different mechanisms of action and resistance profiles may serve to prolong the efficacy of individual drug components and circumvent combination therapy failure. , Even drugs with modest antimalarial efficacy (e.g., antibacterial drugs) , can be considered if they are refractory to resistance development by P. falciparum .…”

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confidence: 99%

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

Lawrence,

Handley,

de Veer

et al. 2024

ACS Infect. Dis.

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The control of malaria, a disease caused by Plasmodium parasites that kills over half a million people every year, is threatened by the continual emergence and spread of drug resistance. Therefore, new molecules with different mechanisms of action are needed in the antimalarial drug development pipeline. Peptides developed from host defense molecules are gaining traction as anti-infectives due to theood of inducing drug resistance. Human platelet factor 4 (PF4) has intrinsic activity against P. falciparum, and a macrocyclic helix−loop−helix peptide derived from its active domain recapitulates this activity. In this study, we used a stepwise approach to optimize first-generation PF4-derived internalization peptides (PDIPs) by producing analogues with substitutions to charged and hydrophobic amino acid residues or with modifications to terminal residues including backbone cyclization. We evaluated the in vitro activity of PDIP analogues against P. falciparum compared to their overall helical structure, resistance to breakdown by serum proteases, selective binding to negatively charged membranes, and hemolytic activity. Next, we combined antiplasmodial potency-enhancing substitutions that retained favorable membrane and cell-selective properties onto the most stable scaffold to produce a backbone cyclic PDIP analogue with four-fold improved activity against P. falciparum compared to first-generation peptides. These studies demonstrate the ability to modify PDIP to select for and combine desirable properties and further validate the suitability of this unique peptide scaffold for developing a new molecule class that is distinct from existing antimalarial drugs.

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confidence: 99%

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

Lawrence,

Handley,

de Veer

et al. 2024

ACS Infect. Dis.

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Plasmodium falciparum artemisinin resistance: something gained in translation

Hughes,

Waters

2024

Trends in Parasitology

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Malate dehydrogenase in parasitic protozoans: roles in metabolism and potential therapeutic applications

Springer,

Agrawal,

Chang

2024

Essays in Biochemistry

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The role of malate dehydrogenase (MDH) in the metabolism of various medically significant protozoan parasites is reviewed. MDH is an NADH-dependent oxidoreductase that catalyzes interconversion between oxaloacetate and malate, provides metabolic intermediates for both catabolic and anabolic pathways, and can contribute to NAD+/NADH balance in multiple cellular compartments. MDH is present in nearly all organisms; isoforms of MDH from apicomplexans (Plasmodium falciparum, Toxoplasma gondii, Cryptosporidium spp.), trypanosomatids (Trypanosoma brucei, T. cruzi) and anaerobic protozoans (Trichomonas vaginalis, Giardia duodenalis) are presented here. Many parasitic species have complex life cycles and depend on the environment of their hosts for carbon sources and other nutrients. Metabolic plasticity is crucial to parasite transition between host environments; thus, the regulation of metabolic processes is an important area to explore for therapeutic intervention. Common themes in protozoan parasite metabolism include emphasis on glycolytic catabolism, substrate-level phosphorylation, non-traditional uses of common pathways like tricarboxylic acid cycle and adapted or reduced mitochondria-like organelles. We describe the roles of MDH isoforms in these pathways, discuss unusual structural or functional features of these isoforms relevant to activity or drug targeting, and review current studies exploring the therapeutic potential of MDH and related genes. These studies show that MDH activity has important roles in many metabolic pathways, and thus in the metabolic transitions of protozoan parasites needed for success as pathogens.

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The problem of antimalarial resistance and its implications for drug discovery

Cited by 3 publications

References 190 publications

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

Plasmodium falciparum artemisinin resistance: something gained in translation

Malate dehydrogenase in parasitic protozoans: roles in metabolism and potential therapeutic applications

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