Activity-based protein profiling of human and plasmodium serine hydrolases and interrogation of potential antimalarial targets

Davison, Dara; Howell, Steven; Snijders, Ambrosius P.; Deu, Edgar

doi:10.1016/j.isci.2022.104996

Cited by 3 publications

(9 citation statements)

References 135 publications

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“…In this review, we have highlighted recent applications of ABPP that demonstrate its versatility in deconstructing host responses to infection. Activity‐based probes have been successfully deployed to identify host PTMs that regulate cell signaling during infection, [30,38,45–46, 51,53,65] host enzymes that shape pathological processes, [69–73,88] and host targets for antimicrobial therapy [101,105,109,114] . Future advances in probe design will afford expanded coverage of functionally diverse PTMs that impact host–pathogen interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Activity-based probes have been successfully deployed to identify host PTMs that regulate cell signaling during infection, [30,38,45-46, 51,53,65] host enzymes that shape pathological processes, [69][70][71][72][73]88] and host targets for antimicrobial therapy. [101,105,109,114] Future advances in probe design will afford expanded coverage of functionally diverse PTMs that impact host-pathogen interactions. Probes with novel electrophilic warheads and/or recognition elements will add to the growing list of PTMs and enzymes that can be globally profiled using chemical proteomic techniques.…”

Section: Discussionmentioning

confidence: 99%

“…Davison et al. employed ABPP to identify serine hydrolases that are active during asexual replication and could serve as potential antimalarial targets [101] . Chemical proteomic analysis of P. falciparum lysates using an FP‐based probe revealed 25 parasitic and eight host serine hydrolases with variable activity across the erythrocytic cycle, suggesting stage‐specific roles for these enzymes.…”

Section: Host‐directed Therapiesmentioning

confidence: 99%

“…[100] Davison et al employed ABPP to identify serine hydrolases that are active during asexual replication and could serve as potential antimalarial targets. [101] Chemical proteomic analysis of P. falciparum lysates using an FP-based probe revealed 25 parasitic and eight host serine hydrolases with variable activity across the erythrocytic cycle, suggesting stage-specific roles for these enzymes. To evaluate the importance of human serine hydrolases to parasite replication, P. falciparum was treated with commercial inhibitors targeting each of the eight identified host enzymes.…”

Section: Discovery Of Host Drug Targetsmentioning

confidence: 99%

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Activity‐based Tools for Interrogating Host Biology During Infection

Ramanathan

Hatzios

2023

Israel Journal of Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Host‐directed Therapiesmentioning

confidence: 99%

Section: Discovery Of Host Drug Targetsmentioning

confidence: 99%

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Activity‐based Tools for Interrogating Host Biology During Infection

Ramanathan

Hatzios

2023

Israel Journal of Chemistry

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“…The activity of serine hydrolases in parasites was first investigated with a broad spectrum fluorophosphonate-desthiobiotin probe which enabled the identification of over 20 active serine hydrolases in the lysate of late-stage schizont parasites (Elahi et al, 2019). More recently, a fluorphosphonate probe was used to identify serine hydrolases in live parasites at different stages within the life cycle, clearly demonstrating the dynamic regulation of lipolytic serine hydrolases in P. falciparum (Davison et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets

Bennett,

Narwal,

Kabeche

et al. 2024

Preprint

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SummaryMalaria, caused byPlasmodium falciparum,remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. Like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.

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Metabolism of host lysophosphatidylcholine in Plasmodium falciparum –infected erythrocytes

Liu,

Fike,

Dapper

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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The human malaria parasite Plasmodium falciparum requires exogenous fatty acids to support its growth during the pathogenic, asexual erythrocytic stage. Host serum lysophosphatidylcholine (LPC) is a significant fatty acid source, yet the metabolic processes responsible for the liberation of free fatty acids from exogenous LPC are unknown. Using an assay for LPC hydrolysis in P. falciparum –infected erythrocytes, we have identified small-molecule inhibitors of key in situ lysophospholipase activities. Competitive activity-based profiling and generation of a panel of single-to-quadruple knockout parasite lines revealed that two enzymes of the serine hydrolase superfamily, termed exported lipase (XL) 2 and exported lipase homolog (XLH) 4, constitute the dominant lysophospholipase activities in parasite-infected erythrocytes. The parasite ensures efficient exogenous LPC hydrolysis by directing these two enzymes to distinct locations: XL2 is exported to the erythrocyte, while XLH4 is retained within the parasite. While XL2 and XLH4 were individually dispensable with little effect on LPC hydrolysis in situ, loss of both enzymes resulted in a strong reduction in fatty acid scavenging from LPC, hyperproduction of phosphatidylcholine, and an enhanced sensitivity to LPC toxicity. Notably, growth of XL/XLH-deficient parasites was severely impaired when cultured in media containing LPC as the sole exogenous fatty acid source. Furthermore, when XL2 and XLH4 activities were ablated by genetic or pharmacologic means, parasites were unable to proliferate in human serum, a physiologically relevant fatty acid source, revealing the essentiality of LPC hydrolysis in the host environment and its potential as a target for anti-malarial therapy.

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Activity-based protein profiling of human and plasmodium serine hydrolases and interrogation of potential antimalarial targets

Cited by 3 publications

References 135 publications

Activity‐based Tools for Interrogating Host Biology During Infection

Activity‐based Tools for Interrogating Host Biology During Infection

Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets

Metabolism of host lysophosphatidylcholine in Plasmodium falciparum –infected erythrocytes

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