Integrated investigation of inhibitors active on infectious diseases: insights into molecular and cellular mechanisms of function

• Grant number: 24/04805-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2025
• End date: January 31, 2029
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Rafael Victorio Carvalho Guido
• Principal researcher abroad: Matthias Rottmann
• Institution abroad: Swiss Tropical and Public Health Institute, Switzerland
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Pesquisadores principais: Alessandro Silva Nascimento ; Glaucius Oliva
• Associated researchers: Andre Luis Berteli Ambrosio ; Anna Caroline Campos Aguiar ; Arlene Gonçalves Corrêa ; Carlos Alberto Montanari ; Carlos Roque Duarte Correia ; Luiz Carlos Dias ; Nubia Boechat

Abstract

Infectious diseases have shaped the course of human history and continue to pose significant challenges to global health. They are caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi and are responsible for a significant proportion of deaths worldwide. Malaria is a parasitic infection widespread in tropical and subtropical regions of the world. Due to its high mortality rates, it represents a significant global public health problem. The emergence of resistance to artemisinin-based combination therapies , which has now spread to Africa, is a serious threat to malaria containment efforts and underscores the need to find efficient alternatives. The rise of antimicrobial resistance, coupled with a decrease in the discovery of novel antibiotics, raises the specter of a post-antibiotic era, where even minor injuries could prove fatal. Six pathogens (E. coli, S. aureus, K. pneumoniae, S. pneumoniae, A. baumannii, and P. aeruginosa) are the leading cause of death worldwide. One strategy to address this challenge is to prioritize research and development efforts towards discovering new molecules with antibacterial properties and unique modes of action. Viral infections have had a profound impact on human history and continue to present significant global health challenges. Viruses can cause diseases ranging from the common cold to more severe illnesses such as HIV/AIDS, influenza, and COVID-19. The burden of viral diseases on global health is immense. They are responsible for millions of deaths each year and can cause widespread epidemics or even pandemics, leading to significant socio-economic disruption. This proposal is based on the early drug discovery and development process and is focused on the elucidation of the mechanism of action of inhibitors active on infectious disease. We will investigate previously identified molecular targets from key pathogenic agents including Plasmodium falciparum, Gram-positive and -negative bacteria (E. coli, P. aeruginosa, K. pneumoniae, and A. baumannii), and viruses (SARS-CoV-2, ZIKV, YFV, and CHKV) to shed light on the molecular and cellular mechanism of function. State-of-the-art methods in organic synthesis, cell biology, medicinal chemistry, structural biology will be applied to unravel the mechanism of action of the inhibitors and discover new ones.The Sao Carlos Institute of Physics at the University of São Paulo has a world-renowned structural biology and medicinal chemistry program, providing state-of-the-art facilities for discovering and developing inhibitors as lead candidates. Our facilities are well-equipped to support all steps of this proposal. Our laboratory is a center of excellence of the MMV, which screens all MMV portfolio compounds for activity against the strains of malaria currently circulating in Brazil. Additionally, we have collaborated with DNDi to deliver new alternatives for the treatment of other endemic diseases, including viral infections.The Parasite Chemotherapy Unit of the Swiss Tropical and Public Health Institute is a drug discovery center for protozoan parasites. The PCU has over 25 years of experience in assay development and drug efficacy testing for the causative agents of malaria, African sleeping sickness, Chagas disease, and leishmaniasis. Primary and secondary in vitro assays are combined with mouse models of disease and molecular approaches to drug action and resistance. Also the PCU serves as a reference center for MMV, and we have been key to developing several new drug candidates for malaria, including arterolane, artefenomel, cipargamine and ganaplacide.Therefore, the FAPESP-SNSF grant will be an attractive opportunity for our groups to contribute to global health challenges by investigating new modes of action of inhibitors. Our findings will pave the way for the discovery and development of the next generation of drugs active on infectious diseases. (AU)