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

Víctor M Castillo-Acosta,Sandra Liekens,Yasuhiro Igarashi,Juan Etxebarria,Niels C Reichardt,Miguel Navarro,Dolores González-Pacanowska,Luis M Ruiz-Pérez,Jan Balzarini,David Sacks

doi:10.1371/journal.ppat.1005851

Abstract

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.

Highlights

Human African trypanosomiasis or sleeping sickness is a neglected disease caused by the protozoan parasite Trypanosoma brucei
Trypanosoma brucei, the causative agent of African trypanosomiasis, is coated with a dense layer of the variant surface glycoprotein (VSG), which plays an essential role in antigenic variation and the ability of the parasite to evade the immune system
They are mainly covered by only one kind of a variant surface glycoprotein (VSG) that constitutes an effective barrier that protects from effectors of the host immune system

Summary

Introduction

Human African trypanosomiasis or sleeping sickness is a neglected disease caused by the protozoan parasite Trypanosoma brucei. T. brucei parasites living in the mammalian host rely on antigenic variation to evade the immune system of the host. They are mainly covered by only one kind of a variant surface glycoprotein (VSG) that constitutes an effective barrier that protects from effectors of the host immune system. The VSGs are covered by mannose-rich and complex glycans [2,3,4]. During antigenic variation this shield is changed by expressing new VSGs in a stochastic process known as VSG switching

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