Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets,Cell Chemical Biology

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Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2024-08-12 , DOI: 10.1016/j.chembiol.2024.07.006
John M Bennett ₁ , Sunil K Narwal ₂ , Stephanie Kabeche ₃ , Daniel Abegg ₄ , Vandana Thathy ₂ , Fiona Hackett ₅ , Tomas Yeo ₂ , Veronica L Li ₁ , Ryan Muir ₆ , Franco Faucher ₁ , Scott Lovell ₆ , Michael J Blackman ₇ , Alexander Adibekian ₄ , Ellen Yeh ₈ , David A Fidock ₉ , Matthew Bogyo ₁₀

Affiliation

Department of Chemistry, Stanford University, Stanford, CA, USA.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, NY, USA.
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA.
Malaria Biochemistry Laboratory, Francis Crick Institute, London NW1 1AT, UK.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Malaria Biochemistry Laboratory, Francis Crick Institute, London NW1 1AT, UK; Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, NY, USA; Division of Infectious Diseases, Columbia University Medical Center, New York, NY 10032, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. 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 promising, synthetically tractable antimalarials.

中文翻译：

混合烷基/芳基膦酸盐将代谢性丝氨酸水解酶确定为抗疟靶点

由恶性疟原虫引起的疟疾仍然是一个重大的健康负担。开发抗疟药的一个主要障碍是寄生虫迅速产生耐药性的能力。我们之前证明，salinipostin A （SalA）是一种天然产物，通过抑制多种脂质代谢丝氨酸水解酶有效杀死寄生虫，这种机制导致耐药倾向低。鉴于使用天然产物作为治疗剂的困难，我们合成了一个小的脂质混合烷基/芳基膦酸盐库作为 SalA 的生物等排体。两种结构异构体表现出不同的抗寄生虫效力，能够识别治疗相关的靶点。该活性化合物通过一种不同于 SalA 和泛脂肪酶抑制剂奥利司他的机制杀死寄生虫，并显示出与奥利司他的协同杀伤作用。我们的化合物仅诱导弱耐药性，这归因于参与多药耐药性的单个蛋白质的突变。这些数据表明，混合烷基/芳基膦酸盐是有前途的、合成易处理的抗疟药。

更新日期：2024-08-12

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