Carbohydrate-Binding Non-Peptidic Pradimicins for the Treatment of Acute Sleeping Sickness in Murine Models.
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.
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
Víctor M
VM
Castillo-Acosta
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
Luis M
LM
Ruiz-Pérez
Glycotechnology Laboratory, CIC biomaGUNE, Parque Científico y Tecnológico de Gipuzkoa, San Sebastián, Spain.
Juan
http://orcid.org/0000-0002-5359-8873
J
Etxebarria
Glycotechnology Laboratory, CIC biomaGUNE, Parque Científico y Tecnológico de Gipuzkoa, San Sebastián, Spain.|CIBER of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), San Sebastián, Spain.
Niels C
NC
Reichardt
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
Miguel
http://orcid.org/0000-0003-2301-2699
M
Navarro
Biotechnology Research Center, Toyama Prefectural University, Imizu, Toyama, Japan.
Yasuhiro
Y
Igarashi
KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.
Sandra
S
Liekens
KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.
Jan
J
Balzarini
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
Dolores
http://orcid.org/0000-0002-4303-5209
D
González-Pacanowska
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