Search for antiviral drug candidate compounds targeting the Monkeypox virus replication complex (DNA polymerase)

• Grant number: 25/00796-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2025
• End date: May 31, 2028
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Glaucius Oliva
• Grantee: Bianca Righetti da Silva
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

In May 2022, the World Health Organization (WHO) was informed of a confirmed case of monkeypox (MPOX) caused by the Monkeypox virus (MPXV) in the United Kingdom, followed by a rapid spread of the disease to other countries. Until November 2024, 117,663 cases had been confirmed worldwide, 13,236 of which were in Brazil alone. Transmission of MPXV typically occurs between people or wild animals, through contact with injuries, body fluids, respiratory droplets or contaminated materials. The drug Tecovirimat and the Jynneos vaccine have been used on an emergency basis to combat monkeypox. Although they were approved in 2024 by European, Brazilian, and U.S. health authorities, data from animal and human studies are still not fully available. Therefore, several aspects, such as potential complications, dosage, and long-term effects, still need to be evaluated. The Monkeypox virus has a 197 kb genome, belongs to the Orthopoxvirus genus within the Poxviridae family, and possesses double-stranded DNA. This virus contains two essential polymerases: a DNA polymerase (DNApol) and a DNA-dependent RNA polymerase (DdRp). DNApol is considered one of the most critical enzymes in the viral cycle because it is directly involved in replication. Additionally, its synthesis occurs early in the infection process, making this enzyme a significant pharmacological target. Thus, the main objective of this project is to perform the biophysical, functional, and structural characterization of the DNA polymerase complex of the MPXV virus, aiming to identify inhibitors through the standardization of kinetic and structural assays. The ultimate goal is to obtain valuable information that can serve as a basis for structure-based drug design targeting this enzyme.