Targeting neglected diseases: Technological approaches for development of therapeutic strategies

Neglected tropical diseases (NTDs) are a significant burden on the economy, public health systems and overall quality-of-life in developing countries worldwide. Many important arthropod-borne viral diseases are NTDs, such as Dengue, Chikungunya, Zika and Yellow Fever. Risk of epidemics and reduced knowledge regarding these viruses calls for the development of therapeutic strategies against arboviral NTDs. Here we present two approaches for the search of potential treatments against arboviral infections: the development of High-Throughput Screening (HTS) assays for drug repurposing and the development of new chemokine-derived molecules aiming at understudied antiviral targets.

We tested over 1000 compounds from the NIH Clinical Collection and MMV Covid Box libraries using phenotypic HTS assays against three arboviruses (Mayaro Virus, Togaviridae; Saint-Louis Encephalitis Virus, Flaviviridae; and Oropouche Virus, Peribunyaviridae). An average 20 hit candidates showed at least 50% protection from virus-induced cell death, for each infection. Hits with best antiviral and/or protective activity were further evaluated in vitro and in vivo in experimental models previously established in the lab. We also present the development and investigation of new antiviral candidate molecules based on CXCL9, a pro-inflammatory chemokine with GAG-binding properties, that may act as a competitive inhibitor of virus binding to host cells. CXCL9-derived peptides consisted of carboxy-terminal residues 74 to 103, synthesized with L- or D-aminoacids as monomers or dimers, and a variation in which all lysines were substituted by ornithines. Synthesis of these molecules were successful and our preliminary results show that CXCL9-derived peptides built with D-aminoacids were resistant to protease cleavage up to 6h of incubation. Both strategies represent technological advancements in the study of therapeutic strategies against arboviral NTDs. HTS assays for drug repurposing are a fast and cost-effective method to scan candidate compounds from libraries of drugs already approved for human use, offering solutions for unmet medical needs. Development of new CXCL9-derived molecules may pave the way to a new class of antiviral compounds and therapeutic strategies mediated by this chemokine.

Authors

Ana Carolina de Carvalho(1,2), Emily Slowikowski(2), Alexandre Borin Pereira(1), Giuliana E. Sotorilli(1), Laís Durço Coimbra(1), Rebeca P. F. Rocha(1), Paul Proost(2), Rafael Elias Marques(1)

Organisations

"1.Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil. 2.Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium. "

Presenting author

Ana Carolina De Carvalho, PhD, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
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