A multi-platform prospection for a treatment against rabies

• Grant number: 22/07115-7
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2022
• End date: November 30, 2025
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Preventive Veterinary Medicine
• Principal Investigator: Paulo Eduardo Brandão
• Grantee: Paulo Eduardo Brandão
• Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Gladys Viviana Parreño ; Sheila Oliveira de Souza ; Sueli Akemi Taniwaki Miyagi

Abstract

Despite its 100% lethality and the circa 59,000 human deaths every year, rabies is still in want of an effective treatment. A host of trials is described aiming at impairing the life cycle of Lyssavirus rabies (RABV), the chief worldwide lyssavirus causing rabies, but with limited success. Treatments targeting host factors and to circumvent the lesions caused by RABV have also shown unsatisfactory. As an attempt to shed some light on the treatment of rabid patients, this application's aims a. to assess the effect of the intracerebral transfection of anti-RABV recombinant monoclonal nanobodies as antivirals against rabies in vivo in a post-exposition protocol, b. to select in silico antiviral candidates against RABV using molecular docking and molecular dynamics and c. to test in vitro, in cell cultures, the selected antiviral candidates against RABV, obtained by molecular docking and dynamic and drug repurposing. Molecular dynamics will be run with the ligands Platyphylline, Rufloxacin, 2,3-dehydroofloxacin and 2-[4-(4-Morpholinylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dione and all RABV proteins (N, P, M, G and L). The in vitro assays will be run in N2A cells inoculated with the PV strain of RABV using the repurposed drugs Methotrexate hydrate, Pitstop 2, Diclazuril or 2,3-dehydroofloxacin. For the in vivo assay, mice intranasally inoculated with the CVS strain of RABV will be injected via the intracerebral route with six different anti-RABV llama-derived nanobodies complexed with a transfection agent. It is expected that the outcomes of this application might improve the candidate anti-RABV protocols already available, such as antibody delivery, the surveying of antiviral candidates in silico and the running of trials on repurposed antiviral drugs, all low-cost proxies to a rational treatment for rabies. (AU)