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Determination of substrate specificity of plasma membrane transporters from Saccharomyces cerevisiae and Homo sapiens

Grant number: 17/01986-8
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2017
Effective date (End): July 31, 2021
Field of knowledge:Biological Sciences - Biology
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Elizabeth Bilsland
Grantee:Ludimila Dias Almeida
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:15/03553-6 - Engineering yeast cells for drug discovery, AP.JP
Associated scholarship(s):18/09194-6 - Identification of plasma membrane import routes of Tau, FUS and alpha-synuclein disaggregating compounds using yeast based high-content screening, BE.EP.DR

Abstract

Drugs need to reach their targets (present on the surface or inside the cells) in order to function. Traditionally the pharmaceutical industry has designed new compounds assuming that they would enter the cell by passive diffusion through the plasma membrane, however, there is a growing body of evidence indicating that passive diffusion entry is the exception rather than the rule. Studies indicate that the entry occurs preferentially by the action of carrier proteins in a facilitated transport process. The passage through the blood-brain barrier in particular presents one of the greatest challenges in the development of drugs directed to the central nervous system, as this tissue separates the blood circulation from the interstitial space of the brain, aiming at protection against toxic substances and invading organisms. The knowledge of the specificity of the transporters found in the barrier cells is very important in the correct targeting of drugs in nerve cells. Saccharomyces cerevisiae yeast is a model organism that has been used in chemogenomics for the understanding of the mechanisms of action and transport of drugs. The study of the specificity of yeast transporters is of great importance for the design of drugs, due to the existence of human orthologs of these proteins. In this context, the project aims to define the substrate specificity of 121 non-essential yeast transporters. We aimed to utilize a newly constructed library of lineages containing deletions in pairs from nonessential yeast transporters for the determination of the specificity of these proteins to a library of compounds and commercial drugs of the central nervous system. We will also study the specificity of human orthologous transporters, combining laboratory experiments and bioinformatics. The project will provide a basis for the design of new drugs for both pathogenic yeasts and human targets. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALMEIDA, LUDIMILA DIAS; SILVA, ALI SALIM FARAJ; MOTA, DANIEL CALIXTO; VASCONCELOS, ADRIELLE AYUMI; CAMARGO, ANTONIO PEDRO; PIRES, GABRIEL SILVA; FURLAN, MONIQUE; FREIRE, HELENA MARTINS RIBEIRO DA CUNHA; KLIPPEL, ANGELICA HOLLUNDER; SILVA, SUELEN FERNANDES; et al. Yeast Double Transporter Gene Deletion Library for Identification of Xenobiotic Carriers in Low or High Throughput. MBIO, v. 12, n. 6, . (17/13015-7, 19/14146-3, 17/01986-8, 18/04240-0, 18/05328-8, 18/16672-1, 15/03553-6, 19/17876-2)
FERREIRA, LETICIA T.; VENANCIO, VINICIUS P.; KAWANO, TAILA; ABRAO, LAILAH C. C.; TAVELLA, TATYANA A.; ALMEIDA, LUDIMILA D.; PIRES, GABRIEL S.; BILSLAND, ELIZABETH; SUNNERHAGEN, PER; AZEVEDO, LUCIANA; et al. Chemical Genomic Profiling Unveils the in Vitro and in Vivo Antiplasmodial Mechanism of Acai (Euterpe oleracea Mart.) Polyphenols. ACS OMEGA, v. 4, n. 13, p. 15628-15635, . (15/03553-6, 17/01986-8, 17/18611-7, 17/50400-6, 18/07007-4)
FERREIRA, LETICIA TIBURCIO; RODRIGUES, JULIANA; CASSIANO, GUSTAVO CAPATTI; TAVELLA, TATYANA ALMEIDA; PERALIS TOMAZ, KAIRA CRISTINA; BAIA-DA-SILVA, DJANE CLARYS; SOUZA, MACEJANE FERREIRA; DO NASCIMENTO LIMA, MARILIA NUNES; MOTTIN, MELINA; ALMEIDA, LUDIMILA DIAS; et al. Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax. Antimicrobial Agents and Chemotherapy, v. 64, n. 9, . (17/02031-1, 18/24878-9, 13/13119-6, 15/03553-6, 17/01986-8, 15/20774-6)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ALMEIDA, Ludimila Dias. Saccharomyces cerevisiae, uma plataforma para descobrimento de drogas: desde a seleção de compostos ativos à identificação de rotas de transporte. 2022. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.

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