Carbohydrate-Binding Non-Peptidic Pradimicins for the Treatment of Acute Sleeping Sickness in Murine Models

PLoS Pathogens

Sandra Liekens¹  Miguel Navarro²  Juan Etxebarria³  Niels C. Reichardt³  Yasuhiro Igarashi⁴  Víctor M. Castillo-Acosta⁴  Luis M. Ruiz-Pérez⁴  Jan Balzarini⁵  Dolores González-Pacanowska⁵ 

[1] Biotechnology Research Center, Toyama Prefectural University, Imizu, Toyama, Japan;CIBER of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), San Sebastián, Spain;Glycotechnology Laboratory, CIC biomaGUNE, Parque Científico y Tecnológico de Gipuzkoa, San Sebastián, Spain;Instituto de Parasitología y Biomedicina “López-Neyra”, Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain;KU Leuven, Rega Institute for Medical Research, Leuven, Belgium

关键词: Parasitic diseases;    Trypanosoma;    Trypanosoma brucei gambiense;    Lectins;    Endocytosis;    Glycosylation;    Mouse models;    Glycoproteins;   

DOI  :  10.1371/journal.ppat.1005851

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Current treatments available for African sleeping sickness or human African trypanosomiasis (HAT) are limited, with poor efficacy and unacceptable safety profiles. Here, we report a new approach to address treatment of this disease based on the use of compounds that bind to parasite surface glycans leading to rapid killing of trypanosomes. Pradimicin and its derivatives are non-peptidic carbohydrate-binding agents that adhere to the carbohydrate moiety of the parasite surface glycoproteins inducing parasite lysis in vitro. Notably, pradimicin S has good pharmaceutical properties and enables cure of an acute form of the disease in mice. By inducing resistance in vitro we have established that the composition of the sugars attached to the variant surface glycoproteins are critical to the mode of action of pradimicins and play an important role in infectivity. The compounds identified represent a novel approach to develop drugs to treat HAT.

【 授权许可】

CC BY