Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Animals Antimalarials / chemical synthesis Drug Development Malaria, Falciparum / drug therapy Mice Models, Molecular Molecular Conformation Parasitic Sensitivity Tests Plasmodium falciparum / drug effects Proteasome Endopeptidase Complex / metabolism Proteasome Inhibitors / chemical synthesis
inhibitors malaria proteasome selectivity therapeutics

Journal

Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543

Informations de publication

Date de publication:
19 04 2021
Historique:
revised: 29 12 2020
received: 27 11 2020
pubmed: 13 1 2021
medline: 10 8 2021
entrez: 12 1 2021
Statut: ppublish

Résumé

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice.

Identifiants

DOI: 10.1002/anie.202015845 PMID: 33433953 PMC: PMC8087158
pubmed: 33433953
doi: 10.1002/anie.202015845
pmc: PMC8087158
mid: NIHMS1692489
doi:

Substances chimiques

Antimalarials 0
Proteasome Inhibitors 0
Proteasome Endopeptidase Complex EC 3.4.25.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

9279-9283

Subventions

Organisme : NIAID NIH HHS
ID : R21 AI123794
Pays : United States
Organisme : NIH HHS
ID : AI139179
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI139179
Pays : United States
Organisme : NIH HHS
ID : T37MD003407
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI143714
Pays : United States

Informations de copyright

© 2021 Wiley-VCH GmbH.

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Auteurs

Wenhu Zhan (W)

Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

Hao Zhang (H)

Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

John Ginn (J)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Annie Leung (A)

Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

Yi J Liu (YJ)

Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

Mayako Michino (M)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Akinori Toita (A)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Rei Okamoto (R)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Tzu-Tshin Wong (TT)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Toshihiro Imaeda (T)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Ryoma Hara (R)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Takafumi Yukawa (T)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Sevil Chelebieva (S)

Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, 94901, USA.

Patrick K Tumwebaze (PK)

Infectious Diseases Research Collaboration, Kampala, Uganda.

Maria Jose Lafuente-Monasterio (MJ)

Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.

Maria Santos Martinez-Martinez (MS)

Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.

Jeremie Vendome (J)

Schrödinger, Inc., New York, NY, 10036, USA.

Thijs Beuming (T)

Schrödinger, Inc., New York, NY, 10036, USA.

Kenjiro Sato (K)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Kazuyoshi Aso (K)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Philip J Rosenthal (PJ)

Department of Medicine, University of California, San Francisco, CA, 94143, USA.

Roland A Cooper (RA)

Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, 94901, USA.

Peter T Meinke (PT)

Tri-Institutional Therapeutics Discovery Institute, 413 E 69th St, New York, NY, 10065, USA.

Carl F Nathan (CF)

Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

Laura A Kirkman (LA)

Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

Gang Lin (G)

Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.
ORCID: 0000-0003-4797-7073

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiparasitaires › Antiprotozoaires › Antipaludiques › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Infection › Maladies vectorielles › Paludisme › Paludisme à Plasmodium falciparum › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité parasitaire › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Eucaryotes › Alveolata › Apicomplexa › Haemosporida › Plasmodium › Plasmodium falciparum › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Proteasome endopeptidase complex › Development of a Highly Selective Plasmodium...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéases › Inhibiteurs du protéasome › Development of a Highly Selective Plasmodium...