Study of fungal chemodiversity and its protease inhibitor potential aiming to discover new antiparasitic and antiviral compounds

• Grant number: 24/01273-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2024
• End date: December 31, 2027
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Paulo Cézar Vieira
• Grantee: Gabriela de Oliveira Almeida
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Natural products are compounds with prominent biological interactions. Their high complexity and chemical diversity have made them promising sources for the development of pharmacological therapies. Proteases are enzymes that catalyze the hydrolysis of peptide bonds. Among the different classes of proteases, cysteine proteases make up a subclass that is comprised of the amino acid cysteine in their catalytic site. Notably, the papain-like cysteine proteases (PLCPs) are the most abundant and can be found in almost all living organisms. Cysteine proteases participate in several biological processes and their imbalance is strongly related to increased proteolytic activity which consequently, leads to the development of some diseases. Interestingly, such enzymes' activities are linked to parasitic infections that cause neglected tropical diseases (NTDs), replication and spread of SARS-CoV-2 - the COVID-19 virus. Therefore, the search for protease inhibitors is a promising strategy for the development of new drugs. There is a high concentration of PLCPs in edible fruits such as papaya and pineapple which play an important protective role against pathogens. In this context, it was observed that some pathogenic fungi biosynthesis specialized compounds that inhibit the proteases present in these fruits, potentially infecting them. To access these substances, this project foresees variation in the cultivation and co-cultivation conditions of fungi. This decision is informed by several observations reported in the literature on the capacity of culture variations leading to inducement or activation of silent biosynthetic routes thus, allowing the production of new bioactive metabolites. Therefore, the aim is to bioprospect substances that inhibit cysteine proteases from the chemodiversity of pathogenic fungi in edible fruits by changing cultivation and co-cultivation conditions. A number of techniques will be utilized for the isolation and characterization of metabolites, including chromatographic (HPLC), spectroscopic (NMR) and spectrometric (mass spectrometry) techniques. The inhibitory activity of papain and other cysteine proteases of parasitic agents and human cathepsins of the isolated compounds will be evaluated, as well as their activity on NTD parasites and SARS-CoV-2. Bioprospecting will also be carried out for metabolites with antifungal action synthesized by fungi when placed in co-cultivation conditions between different species.