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.
Funding: This work was supported by grants from the VI Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, Instituto de Salud Carlos III - Subdirección General de Redes y Centros de Investigación Cooperativa, Red de Investigación Cooperativa en Enfermedades Tropicales (RICET) (RD06/0021), the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (SAF2013-48999-R) (http://www.idi.mineco.gob.es), and the Junta de Andalucía (BIO-199, P09-CVI-5367) to DGP. Research of JB and SL was supported by the Katholieke Universiteit Leuven (PF 10/18). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.