The antimalarial resistome – finding new drug targets and their modes of action

Carolino, Krypton; Winzeler, Elizabeth A.

doi:10.1016/j.mib.2020.06.004

Cited by 46 publications

(39 citation statements)

References 53 publications

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“…Given this consensus and historical and recent clinical findings, it is unwise to ignore MIR and related preclinical data. However, it is counterproductive to impose criteria so stringent that only candidates with neither observable cross-resistance nor a resistance marker (so-called irresistibles) are progressed [27]. Instead, it is important both to down-prioritize those with the greatest intrinsic risk and to accept other candidates along with a well-characterized resistance risk assessment that facilitates further combination decision-making.…”

Section: Trends In Parasitologymentioning

confidence: 99%

Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials

Duffey

Blasco

Burrows

et al. 2021

Trends in Parasitology

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Artemisinin-based combination therapies are first-line treatments for uncomplicated Plasmodium falciparum malaria. However, during the past decade, partial resistance to artemisinins, mediated by PfK13 mutations, has spread across Southeast Asia and emerged in South America, the Western Pacific, and Africa. The emergence of resistance to partner drugs has led to frequent treatment failures in Southeast Asia.

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Section: Trends In Parasitologymentioning

confidence: 99%

Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials

Duffey

Blasco

Burrows

et al. 2021

Trends in Parasitology

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“…However, it has been facing extreme challenges with the emergence and spread of drug-resistant strains for most of the commercially available antimalarial drugs, creating a heavy burden for public health and economic development ( Menard and Dondorp, 2017 ). It holds the advantage that understanding of MoA will enhance drug development by monitoring their activities and resistance to facilitate further clinical use, including the optimization of dose and pharmacokinetics, guiding the selection of partner drugs, and strategy development for combating the emergence of resistances ( Carolino and Winzeler, 2020 ). Capturing influenced metabolome may also inform us about the biology of specific strains with varied drug resistance, providing a catalog of candidate targets or pathways to advance critical malarial-control explorations ( Figure 3B ).…”

Section: Finding Network: Inferring From Antimalarial Moas To Drug Rmentioning

confidence: 99%

From Metabolite to Metabolome: Metabolomics Applications in Plasmodium Research

Feng

Cao

2021

Front. Microbiol.

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Advances in research over the past few decades have greatly improved metabolomics-based approaches in studying parasite biology and disease etiology. This improves the investigation of varied metabolic requirements during life stages or when following transmission to their hosts, and fulfills the demand for improved diagnostics and precise therapeutics. Therefore, this review highlights the progress of metabolomics in malaria research, including metabolic mapping of Plasmodium vertebrate life cycle stages to investigate antimalarials mode of actions and underlying complex host-parasite interactions. Also, we discuss current limitations as well as make several practical suggestions for methodological improvements which could drive metabolomics progress for malaria from a comprehensive perspective.

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“…Currently, artemisinin and its derivatives ( 87 – 93 ) are widely used throughout the world as antimalarial drugs against the protozoan parasites [ 174 , 175 , 176 , 177 ]. An interesting mechanism of action for these compounds appears to involve heme-mediated degradation of the endoperoxide bridge to form carbon-centered free radicals, and these free radicals are selectively toxic to malaria parasites [ 178 , 179 , 180 ]. Artemisinin and its derivatives exhibit antitumor, antifungal, and other activities [ 181 , 182 , 183 ].…”

Section: Polycyclic Endoperoxides Derived From Plants and Liverwormentioning

confidence: 99%

Antiprotozoal and Antitumor Activity of Natural Polycyclic Endoperoxides: Origin, Structures and Biological Activity

et al. 2021

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Polycyclic endoperoxides are rare natural metabolites found and isolated in plants, fungi, and marine invertebrates. The purpose of this review is a comparative analysis of the pharmacological potential of these natural products. According to PASS (Prediction of Activity Spectra for Substances) estimates, they are more likely to exhibit antiprotozoal and antitumor properties. Some of them are now widely used in clinical medicine. All polycyclic endoperoxides presented in this article demonstrate antiprotozoal activity and can be divided into three groups. The third group includes endoperoxides, which show weak antiprotozoal activity with a reliability of up to 70%, and this group includes only 1.1% of metabolites. The second group includes the largest number of endoperoxides, which are 65% and show average antiprotozoal activity with a confidence level of 70 to 90%. Lastly, the third group includes endoperoxides, which are 33.9% and show strong antiprotozoal activity with a confidence level of 90 to 99.6%. Interestingly, artemisinin and its analogs show strong antiprotozoal activity with 79 to 99.6% confidence against obligate intracellular parasites which belong to the genera Plasmodium, Toxoplasma, Leishmania, and Coccidia. In addition to antiprotozoal activities, polycyclic endoperoxides show antitumor activity in the proportion: 4.6% show weak activity with a reliability of up to 70%, 65.6% show an average activity with a reliability of 70 to 90%, and 29.8% show strong activity with a reliability of 90 to 98.3%. It should also be noted that some polycyclic endoperoxides, in addition to antiprotozoal and antitumor properties, show other strong activities with a confidence level of 90 to 97%. These include antifungal activity against the genera Aspergillus, Candida, and Cryptococcus, as well as anti-inflammatory activity. This review provides insights on further utilization of polycyclic endoperoxides by medicinal chemists, pharmacologists, and the pharmaceutical industry.

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The antimalarial resistome – finding new drug targets and their modes of action

Cited by 46 publications

References 53 publications

Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials

Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials

From Metabolite to Metabolome: Metabolomics Applications in Plasmodium Research

Antiprotozoal and Antitumor Activity of Natural Polycyclic Endoperoxides: Origin, Structures and Biological Activity

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