Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

Summers, Robert L.; Pasaje, Charisse Flerida A.; Pisco, João Pedro; Striepen, Josefine; Luth, Madeline R.; Kümpornsin, Krittikorn; Carpenter, Emma F.; Munro, Justin T.; Lin, De; Plater, Andrew; Punekar, Avinash S.; Shepherd, Andrew; Shepherd, Sharon M.; Vanaerschot, Manu; Murithi, James M.; Rubiano, Kelly; Akidil, Aslı; Ottilie, Sabine; Mittal, Nimisha; Dilmore, Amanda Hazel; Won, Madalyn M.; Mandt, Rebecca; McGowen, Kerry; Owen, Edward; Walpole, Chris; Llinás, Manuel; Lee, Marcus; Winzeler, Elizabeth A.; Fidock, David A.; Gilbert, Ian H.; Wirth, Dyann F.; Niles, Jacquin C.; Baragaña, Beatriz; Lukens, Amanda K.

doi:10.1016/j.chembiol.2021.07.010

Cited by 62 publications

(64 citation statements)

References 52 publications

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“…falciparum parasites treated with the iPanAm MMV689258, acetyl-CoA levels were reduced while CoA levels remained stable. Furthermore, induction of resistance to iPanAms led to mutations in the acetyl-CoA synthetase (AcAS [ 127 ]) and acyl-CoA synthetase 11 (ACS11). Confirmation of the role of these mutations in drug sensitivity using CRISPR-Cas9 gene editing in combination with extensive metabolomic profiling demonstrated that PanAms are also converted into CoA-PanAms, and, recently, it has been conclusively shown that these CoA-PanAms inhibit AcAS activity ( Fig 4 ) [ 35 , 99 , 100 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, the exact downstream effects remain unknown. Although AcAS was identified as a target, there are 3 common enzymes and complexes in Toxoplasma and Plasmodium parasites that are able to produce acetyl-CoA and may therefore be targeted by CoA-PanAms: (i) the mitochondrial branched chain ketoacid dehydrogenase (BCKDH) complex [ 17 , 34 , 128 ]; (ii) the pyruvate dehydrogenase (PDH) complex in the apicoplast [ 129 , 130 ]; and (iii) the cytosolic and nuclear AcAS [ 100 , 127 , 131 ]. T .…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the third enzyme that produces acetyl-CoA, AcAS, has been convincingly demonstrated to be targeted by CoA-PanAm [ 100 ] and other inhibitors [ 127 ] and is essential in Plasmodium asexual blood stages [ 22 , 127 ]. The essentiality of AcAS and its potent inhibition through PanAms likely explain the deleterious effect of PanAm treatment on Plasmodium .…”

Section: Introductionmentioning

confidence: 99%

“…Both enzymes have been shown to be important for FA elongation (FAE) and N-ε-lysine acetylation of histones and non-histone proteins [ 133 ]. Pf AcAS also provides acetyl-CoA for histone acetylation and has been associated with a chromatin-remodeling complex [ 127 , 131 ]. The FAE pathway is essential for both T .…”

Section: Introductionmentioning

confidence: 99%

“…Triacsin C inhibits Cp ACS1 (cgd3_640) and Cp ACS2 (cgd5_3200) activity [ 158 ], while CoA-PanAms may inhibit Pf ACS11 [ 99 ]. However, the potential of Pf ACS11 as a drug target is still unknown as it is unclear whether ACS11 plays an essential role [ 22 , 127 ]. Additionally, the induction of mutations in ACS11 by exposure to chemically unrelated compounds [ 127 , 159 ] suggests that this enzyme may be a general marker of resistance and not the specific target of PanAms.…”

Section: Introductionmentioning

confidence: 99%

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Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

et al. 2021

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The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

et al. 2021

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Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal

Bagratee,

Prawlall,

Ndlovu

et al. 2024

Chemistry & Biodiversity

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Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug‐resistant strains. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

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Another decade of antimalarial drug discovery: New targets, tools and molecules

Woodland,

Horatscheck,

Soares de Melo

et al. 2024

Progress in Medicinal Chemistry

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Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

Cited by 62 publications

References 52 publications

Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal

Another decade of antimalarial drug discovery: New targets, tools and molecules

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