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Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides.
King, Harry R; Bycroft, Mark; Nguyen, Thanh-Binh; Kelly, Geoff; Vinogradov, Alexander A; Rowling, Pamela J E; Stott, Katherine; Ascher, David B; Suga, Hiroaki; Itzhaki, Laura S; Artavanis-Tsakonas, Katerina.
Afiliación
  • King HR; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
  • Bycroft M; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.
  • Nguyen TB; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.
  • Kelly G; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane QLD 4067, Australia.
  • Vinogradov AA; NMR Centre, Francis Crick Institute, London NW1 1AT, United Kingdom.
  • Rowling PJE; Department of Chemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan.
  • Stott K; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.
  • Ascher DB; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
  • Suga H; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane QLD 4067, Australia.
  • Itzhaki LS; Department of Chemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan.
  • Artavanis-Tsakonas K; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.
Proc Natl Acad Sci U S A ; 121(21): e2322923121, 2024 May 21.
Article en En | MEDLINE | ID: mdl-38739798
ABSTRACT
The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, including Plasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disrupt P. falciparum growth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within the Plasmodium ubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Plasmodium falciparum / Proteínas Protozoarias / Ubiquitina Tiolesterasa Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Plasmodium falciparum / Proteínas Protozoarias / Ubiquitina Tiolesterasa Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos