Pharmacology of oligopeptidases and intracellular peptides

• Grant number: 16/04000-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2017
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Emer Suavinho Ferro
• Grantee: Emer Suavinho Ferro
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Leo Kei Iwai
• Associated researchers: Alice Cristina Rodrigues ; Carolina Demarchi Munhoz ; Eliana Hiromi Akamine ; Fabio Cesar Gozzo ; Jair Ribeiro Chagas ; José Cesar Rosa Neto ; Rosana Camarini ; Rosangela Aparecida dos Santos Eichler ; Soraia Katia Pereira Costa ; Vanessa Rioli
• Associated scholarship(s): 19/27149-0 - Knockout mice for thimet oligopeptidase as a model for the study of Obesity and Obesity-associated diseases, BP.PD; 19/24874-6 - Technical training to support the thematic project Pharmacology of Oligopeptidases and Intracellular Peptides, BP.TT; 19/15965-8 - Regulation of the expression of microRNAs by intracellular peptides in the induction of non-alcoholic steatohepatitis in knockout mice for EP24.15, BP.MS; + associated scholarships 19/07332-5 - Structural basis of intracellular peptides-protein interactions, BP.PD; 18/07852-6 - Development and standardization of a new methodology to evaluate the effect of intracellular peptides on protein-protein interactions, BP.PD; 18/06901-3 - Technical training level 2 - 40 hours per week, BP.TT; 17/18080-1 - Technical training in laboratory animal facility general techniques, BP.TT - associated scholarships

Abstract

Oligopeptidases were first described as kininases from rabbit brain in the early 70's by Prof. Antonio C. M. Camargo at USP Ribeirão Preto Medical School. Studies from our research group suggested that more than 90% of thimet oligopeptidase (EC3.4.24.15; EP24.15) and neurolysin (EC3.4.24.16; Nln) are concentrated inside the cells; these data suggested some doubts about the major function of oligopeptidases in generating and degrading neuropeptides such as bradykinin (1-11). The first intracellular function described for EP24.15 was in processing and degradation of antigens associated with major histocompatibility class I complex (12,13), which is now supported by additional studies (14-20). The development and use of a novel substrate-capture assay using catalytically inactive EP2.15 or Nln (21-23) led to hemopressin discovery (24-62), and to further studies on intracellular peptides that could be functional inside the cells (63-78; "Temático" Fapesp 04/04933-2). Here, we intend to investigate the biological significance of intracellular peptides. The main aims are: 1) putative therapeutic use of hemopressin and intracellular peptides, 2) uncover mechanisms related to intracellular peptide action, 3) peptidomic and new methods to quantitate peptides in biological samples, 4) phenotype characterization of C57BL6 knockout mice for EP24.15, Nln and EP24.15/Nln. The potential clinical applications of this knowledge will be a constant goal during the development of this project. (AU)

Scientific publications

(25)

(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)

DASGUPTA, SAYANI; FISHMAN, MICHAEL A.; CASTRO, LEANDRO M.; TASHIMA, ALEXANDRE K.; FERRO, EMER S.; FRICKER, LLOYD D.. Effect of Protein Denaturation and Enzyme Inhibitors on Proteasomal-Mediated Production of Peptides in Human Embryonic Kidney Cells. BIOMOLECULES, v. 9, n. 6, JUN 2019. (16/04000-3, 17/20106-9)

SILVA, RENEE N. O.; LLANOS, RICARDO P.; EICHLER, ROSANGELA A. S.; OLIVEIRA, THIAGO B.; GOZZO, FABIO C.; FESTUCCIA, WILLIAM T.; FERRO, EMER S.. New Intracellular Peptide Derived from Hemoglobin Alpha Chain Induces Glucose Uptake and Reduces Blood Glycemia. PHARMACEUTICS, v. 13, n. 12, DEC 2021. (15/07273-8, 16/04000-3)

GEWEHR, MAYARA C. F.; TEIXEIRA, ALEXANDRE A. S.; SANTOS, BRUNA A. C.; BIONDO, LUANA A.; GOZZO, FABIO C.; CORDIBELLO, AMANDA M.; EICHLER, ROSANGELA A. S.; RECKZIEGEL, PATRICIA; DA SILVA, RENEE N. O.; DOS SANTOS, NILTON B.; et al. The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity. BIOMOLECULES, v. 10, n. 2, FEB 2020. (14/17264-3, 16/04000-3, 04/04933-2, 15/20657-0)

PARADA, CAROLINA A.; DE OLIVEIRA, IVAN PIRES; GEWEHR, MAYARA C. F.; MACHADO-NETO, JOAO AGOSTINHO; LIMA, KELI; EICHLER, ROSANGELA A. S.; LOPES, LUCIA R.; BECHARA, LUIZ R. G.; FERREIRA, JULIO C. B.; FESTUCCIA, WILLIAM T.; et al. ffect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP-FRB Interaction and Autophag. ELL, v. 11, n. 3, FEB 2022. (19/25049-9, 13/07937-8, 19/27149-0, 17/02201-4, 16/04000-3, 19/07332-5, 19/23864-7)

DOS SANTOS, NILTON B.; FRANCO, ROSEANE D.; CAMARINI, ROSANA; MUNHOZ, CAROLINA D.; EICHLER, ROSANGELA A. S.; GEWEHR, MAYARA C. F.; RECKZIEGEL, PATRICIA; LLANOS, RICARDO P.; DALE, CAMILA S.; DA SILVA, VICTORIA R. O.; et al. Thimet Oligopeptidase (EC 3.4.24.15) Key Functions Suggested by Knockout Mice Phenotype Characterization. BIOMOLECULES, v. 9, n. 8, AUG 2019. (16/04000-3, 15/07273-8, 04/04933-2, 15/20657-0)

FERRO, EMER S.; GEWEHR, MAYARA C. F.; NAVON, AMI. Thimet Oligopeptidase Biochemical and Biological Significances: Past, Present, and Future Directions. BIOMOLECULES, v. 10, n. 9, SEP 2020. (16/04000-3)

MANZI TEIXEIRA, CAIO MATHEUS; CORREA, CLAUDIA NEVES; IWAI, LEO KEI; FERRO, EMER SUAVINHO; DE CASTRO, LEANDRO MANTOVANI. Characterization of Intracellular Peptides from Zebrafish (Danio rerio) Brain. ZEBRAFISH, v. 16, n. 3, p. 1-12, APR 2019. (16/04000-3, 15/22752-0)

LIMA, JOANNA D. C. C.; SIMOES, ESTEFANIA; DE CASTRO, GABRIELA; MORAIS, MYCHEL RAONY P. T.; DE MATOS-NETO, EMIDIO M.; ALVES, MICHELE J.; PINTO, I, NELSON; FIGUEREDO, RAQUEL G.; ZORN, TELMA M. T.; FELIPE-SILVA, ALOISIO S.; et al. Tumour-derived transforming growth factor-beta signalling contributes to fibrosis in patients with cancer cachexia. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 10, n. 5, p. 1045-1059, OCT 2019. (16/04000-3, 12/50079-0)

VALENCIA, ALEXY OROZCO; KNIRSCH, MARCOS CAMARGO; FERRO, EMER SUAVINHO; STEPHANO, MARCO ANTONIO. Interleukin-2 as immunotherapeutic in the autoimmune diseases. International Immunopharmacology, v. 81, APR 2020. (16/04000-3)

NAVARRO, MARINA V.; CHAVES, ALISON F. A.; CASTILHO, DANIELE G.; CASULA, ISIS; CALADO, JULIANA C. P.; CONCEICAO, PALLOMA M.; IWAI, LEO K.; DE CASTRO, BEATRIZ F.; BATISTA, WAGNER L.. Effect of Nitrosative Stress on theS-Nitroso-Proteome ofParacoccidioides brasiliensis. FRONTIERS IN MICROBIOLOGY, v. 11, JUN 4 2020. (17/04592-0, 13/07467-1, 16/04000-3, 15/09654-9, 17/17943-6)

MONTONI, FABIO; ANDREOTTI, DIANA ZUKAS; DOS SANTOS EICHLER, ROSANGELA APARECIDA; SANTOS, WELLINGTON DA SILVA; KISAKI, CAROLINA YUKIKO; SUEHIRO ARCOS, STEPHANIE SANTOS; LIMA, ISMAEL FEITOSA; MALTAURO SOARES, MAGNA APARECIDA; NISHIYAMA-JR, MILTON YUTAKA; NAVA-RODRIGUES, DANIEL; et al. The impact of rattlesnake venom on mice cerebellum proteomics points to synaptic inhibition and tissue damage. JOURNAL OF PROTEOMICS, v. 221, JUN 15 2020. (17/17943-6, 13/07467-1, 16/04000-3, 15/50040-4, 17/06496-9)

FIGUEIREDO, D. A. L.; SANTOS, W. S.; MONTONI, FABIO; IWAI, LEO KEI; SILVA JUNIOR, I, P.. Toposome: Source of antimicrobial molecules in the gonads of the sea urchin Lytechinus variegatus (Lamarck, 1816). FISH & SHELLFISH IMMUNOLOGY, v. 109, p. 51-61, FEB 2021. (17/17943-6, 16/04000-3)

HEIMANN, ANDREA S.; DALE, CAMILA S.; GUIMARAES, FRANCISCO S.; REIS, RICARDO A. M.; NAVON, AMI; SHMUELOV, MICHAL A.; RIOLI, VANESSA; GOMES, IVONE; DEVI, LAKSHMI L.; FERRO, EMER S.. Hemopressin as a breakthrough for the cannabinoid field. Neuropharmacology, v. 183, FEB 1 2021. (16/04000-3, 19/06982-6, 17/24304-0)

SILVERIO, RENATA; BARTH, ROBSON; HEIMANN, ANDREA S.; RECKZIEGEL, PATRICIA; DOS SANTOS, GUSTAVO J.; ROMERO-ZERBO, SILVANA Y.; BERMUDEZ-SILVA, FRANCISCO J.; RAFACHO, ALEX; FERRO, EMER S.. Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 8, p. 19-pg., 2022-04-01. (19/25943-1, 16/04000-3)

MARTUCCI, LUIZ FELIPE; EICHLER, ROSANGELA A. S.; SILVA, RENEE N. O.; COSTA, TIAGO J.; TOSTES, RITA C.; BUSATTO, GERALDO F.; SEELAENDER, MARILIA C. L.; DUARTE, ALBERTO J. S.; SOUZA, HERALDO P.; FERRO, EMER S.. Intracellular peptides in SARS-CoV-2-infected patients. ISCIENCE, v. 26, n. 9, p. 17-pg., 2023-09-15. (13/08216-2, 16/04000-3, 17/25116-2)

CAMARGO, LIVIA L.; DENADAI-SOUZA, ALEXANDRE; YSHII, LIDIA M.; LIMA, CARLA; TEIXEIRA, SIMONE A.; CERQUEIRA, ANDERSON R. A.; GEWEHR, MAYARA C. F.; FERNANDES, ELIZABETH S.; SCHENKA, ANDRE A.; MUSCARA, MARCELO N.; et al. The potential anti-inflammatory and anti-nociceptive effects of rat hemopressin (PVNFKFLSH) in experimental arthritis. European Journal of Pharmacology, v. 890, JAN 5 2021. (16/04000-3)

GEWEHR, MAYARA C. F.; SILVERIO, RENATA; ROSA-NETO, JOSE CESAR; LIRA, FABIO S.; RECKZIEGEL, PATRICIA; FERRO, EMER S.. Peptides from Natural or Rationally Designed Sources Can Be Used in Overweight, Obesity, and Type 2 Diabetes Therapies. Molecules, v. 25, n. 5, MAR 1 2020. (16/04000-3, 15/20657-0)

DE ARAUJO, CHRISTIANE B.; HEIMANN, ANDREA S.; REMER, RICARDO A.; RUSSO, LILIAN C.; COLQUHOUN, ALISON; FORTI, FABIO L.; FERRO, EMER S.. Intracellular Peptides in Cell Biology and Pharmacology. BIOMOLECULES, v. 9, n. 4, APR 2019. (16/04000-3, 04/04933-2)

RECKZIEGEL, PATRICIA; FESTUCCIA, WILLIAM T.; BRITTO, LUIZ R. G.; LOPES JANG, KAREN L.; ROMAO, CAROLINA M.; HEIMANN, JOEL C.; FOGACA, MANOELA V.; RODRIGUES, NAIELLY S.; SILVA, NICOLE R.; GUIMARAES, FRANCISCO S.; et al. A novel peptide that improves metabolic parameters without adverse central nervous system effects. SCIENTIFIC REPORTS, v. 7, NOV 1 2017. (15/20657-0, 16/04000-3)

MOREIRA, RAFAEL J.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; BELCHIOR, THIAGO; PEIXOTO, ALBERT S.; CHAVES-FILHO, ADRIANO B.; MORENO, MAYARA F.; LIMA, JANAYNA D.; YOSHINAGA, MARCOS; MIYAMOTO, SAYURI; et al. Lipoatrophy-Associated Insulin Resistance and Hepatic Steatosis are Attenuated by Intake of Diet Rich in Omega 3 Fatty Acids. MOLECULAR NUTRITION & FOOD RESEARCH, v. 64, n. 7, FEB 2020. (13/07467-1, 16/04000-3, 17/17943-6, 15/19530-5, 14/06863-3, 18/15549-1, 13/07937-8)

HEIMANN, ANDREA S.; GIARDINI, A. C.; SANT'ANNA, M. B.; DOS SANTOS, NILTON B.; GEWEHR, MAYARA C. F.; MUNHOZ, CAROLINA D.; CASTRO, LEANDRO M.; PICOLO, GISELE; REMER, RICARDO A.; FERRO, EMER S.. NFKF is a synthetic fragment derived from rat hemopressin that protects mice from neurodegeneration. Neuroscience Letters, v. 721, MAR 16 2020. (16/04000-3)

KISAKI, CAROLINA YUKIKO; ARCOS, STEPHANIE SANTOS SUEHIRO; MONTONI, FABIO; DA SILVA SANTOS, WELLINGTON; CALACINA, HAMIDA MACEDO; LIMA, ISMAEL FEITOSA; CAJADO-CARVALHO, DANIELA; FERRO, EMER SUAVINHO; NISHIYAMA-JR, MILTON YUTAKA; IWAI, LEO KEI. Bothrops Jararaca Snake Venom Modulates Key Cancer-Related Proteins in Breast Tumor Cell Lines. TOXINS, v. 13, n. 8, AUG 2021. (17/06496-9, 13/07467-1, 16/04000-3, 17/17943-6)

SANTOS, W. S.; MONTONI, FABIO; EICHLER, R. A. S.; SUEHIRO ARCOS, STEPHANIE SANTOS; ANDREOTTI, DIANA ZUKAS; KISAKI, CAROLINA YUKIKO; EVANGELISTA, KIMBERLY BORGES; CALACINA, HAMIDA MACEDO; LIMA, ISMAEL FEITOSA; MALTAURO SOARES, MAGNA APARECIDA; et al. Proteomic analysis reveals rattlesnake venom modulation of proteins associated with cardiac tissue damage in mouse hearts. JOURNAL OF PROTEOMICS, v. 258, p. 12-pg., 2022-04-30. (17/06496-9, 13/07467-1, 17/17943-6, 16/04000-3)

SAKAYA, GABRIEL R.; PARADA, CAROLINA A.; EICHLER, ROSANGELA A.; YAMAKI, VITOR N.; NAVON, AMI; HEIMANN, ANDREA S.; FIGUEIREDO, EBERVAL G.; FERRO, EMER S.. Peptidomic profiling of cerebrospinal fluid from patients with intracranial saccular aneurysms. JOURNAL OF PROTEOMICS, v. 240, MAY 30 2021. (16/04000-3, 19/07332-5)

SANTOS, BRUNA A. C.; DA ROCHA, LUCAS A. F.; FERRO, EMER S.; RODRIGUES, ALICE C.. Deletion Of Thimet Oligopeptidase Attenuates Nash Trough Microrna MIR-34a. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 116, p. 1-pg., 2021-01-29. (16/04000-3, 15/24789-8, 19/15965-8)

Filed patent(s) as a result of this research project