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Integrated computational and experimental strategies for the inhibition of exfoliative toxins from Staphylococcus aureus

Grant number: 20/10214-1
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2021
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Raghuvir Krishnaswamy Arni
Grantee:Jorge Enrique Hernández González
Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
Associated scholarship(s):22/03901-8 - Computer-guided identification of inhibitors against staphylococcal exfoliative toxins, BE.EP.PD


Staphylococcus aureus is a bacterium responsible for a wide range of diseases, with the Staphylococcal Scalded Skin Syndrome (SSSS) being one of the most serious. The skin damage in SSSS is caused by S. aureus Exfoliative Toxins (ETs), which are Chymotrypsin-Like Serine Proteases (CLSPs) that cleave the cadherin desmoglein-1 (Dsg-1). Four ETs of the CLSP family have been identified so far in S. aureus strains, the most common serotypes, ETA and ETB, being associated with SSSS in humans. ETD has been related to furuncles and cutaneous abscess and ETE has been found in isolates from ewe mastitis. Unlike most CLSPs, ETs possess an inactive oxyanion hole due to an unusual conformation of residue 192, do not hydrolyze most peptide substrates and are not affected by broad-specificity inhibitors. Previous findings support the oxyanion hole activation prior to Dsg-1 cleavage, which involves the flip of residue 192 triggered by the interaction of ETs with the substrate. As concerns have been raised due to the emergence of ET-encoding S. aureus strains resistant to antibiotics, the search for inhibitors against these proteases as an alternative to traditional antibiotics is greatly needed. Here, we will combine computational and experimental techniques to study various structural and mechanistic features of the ETs that remain elusive to this date that are crucial to the discovery of inhibitors. We intend to build reliable structural models for Dsg-1 complexed with the ETs to probe the activation mechanism of the latter at atomic level. Site-directed mutagenesis will be used to validate our predictions experimentally. Furthermore, virtual screenings of oligopeptide and compound libraries will be conducted in the active site and potential allosteric cavities of the ETs. The best candidates will be tested to identify hits that halt Dsg-1 degradation in vitro. Finally, X-ray diffraction will be employed to gain structural insight into the interaction of ETs with promising hits. Overall, we expect to answer long-standing questions about the activity of ETs and to identify molecules preventing the detrimental effects of these toxins on human and animal health. (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)
GONZALEZ, JORGE ENRIQUE HERNANDEZ; ALBERCA, LUCAS N.; GONZALEZ, YORDANKA MASFORROL; ACOSTA, OSVALDO REYES; TALEVI, ALAN; SALAS-SARDUY, EMIR. Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site. JOURNAL OF CHEMICAL INFORMATION AND MODELING, . (20/10214-1)
HERNANDEZ GONZALEZ, JORGE E.; EBERLE, RAPHAEL J.; WILLBOLD, DIETER; CORONADO, MONIKA A.. Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Proteas. RONTIERS IN MOLECULAR BIOSCIENCE, v. 8, . (20/10214-1)
HERNANDEZ GONZALEZ, JORGE ENRIQUE; SALAS-SARDUY, EMIR; HERNANDEZ ALVAREZ, LILIAN; BARRETO GOMES, DIEGO ENRY; PASCUTTI, PEDRO GERALDO; OOSTENBRINK, CHRIS; LEITE, VITOR B. P.. In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2. Journal of Computer-Aided Molecular Design, v. 35, n. 10, p. 1067-1079, . (16/24587-9, 20/10214-1, 16/19766-1, 18/03911-8, 19/22540-3)

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