Antiviral activity of AAK1 inhibitors against Oropouche infection

• Grant number: 20/02159-0
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): August 01, 2020
• Effective date (End): April 30, 2022
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: José Luiz Proença Módena
• Grantee: Karina Bispo dos Santos
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Oropouche Orthobunyavirus (OROV) is an arbovirus associated with cases of febrile illness in the Amazon region. A high genetic diversity between orthobunyaviruses generated by genetic rearrangement or mutations makes the development of compounds with directly antiviral activity challenging, thus, host-targeted drugs looks a good alternative to develop antivirals against these pathogens. OROV infects hosted cells through clathrin-mediated endocytosis (EMC), a highly orchestrated process, dependent on kinase 1 activity associated with adapter protein 2 (AAK1). Thus, we believe that AAK1 inhibitors may have antiviral activity against OROV. For this purpose, we will determine the antiviral effect of two AAK1 inhibiting compounds and an inhibitor of other non-AAK1 kinases, all non-cytotoxic and with kinase activity verified by SGC-UNICAMP, during the OROV replicative cycle. To identify what stages of viral infection in which these compounds act we will use different pre-treatment and post-treatment protocols in vitro. Morphological characteristics of cells (nucleus, mitochondria and vesicle cells) will be analyzed in the presence and absence of compounds during infection through immunofluorescence confocal microscopy. The data will be validated by silencing and overexpression tests of AAK1 kinase and the most promising compounds will be tested in animal models of OROV infection in future studies. Thus, the project aims to characterize the role of AAK1 in the entry and replication of OROV and to develop a possible antiviral against this emerging patent. (AU)

Scientific publications

(4)

(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)

PASCOAL, LIVIA BITENCOURT; RODRIGUES, PATRICIA BRITO; GENARO, LIVIA MOREIRA; DOS SANTOS PEREIRA GOMES, ARILSON BERNARDO; TOLEDO-TEIXEIRA, DANIEL AUGUSTO; PARISE, PIERINA LORENCINI; BISPO-DOS-SANTOS, KARINA; SIMEONI, CAMILA LOPES; GUIMARAES, PAULA VERI; BUSCARATTI, LUCAS ILDEFONSO; et al. Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples. GUT MICROBES, v. 13, n. 1, p. 1-9, JAN 1 2021. (20/04558-0, 20/04583-4, 20/02448-2, 20/02312-3, 19/14342-7, 20/04746-0, 17/26908-0, 20/04579-7, 20/04919-2, 19/06372-3, 13/07607-8, 20/02159-0)

DE SOUZA, WILLIAM M.; MURARO, STEFANIE P.; SOUZA, GABRIELA F.; AMORIM, MARIENE R.; SESTI-COSTA, RENATA; MOFATTO, LUCIANA S.; FORATO, JULIA; BARBOSA, PRISCILLA P.; TOLEDO-TEIXEIRA, DANIEL A.; BISPO-DOS-SANTOS, KARINA; et al. lusters of SARS-CoV-2 Lineage B.1.1.7 Infection after Vaccination with Adenovirus-Vectored and Inactivated Vaccine. Viruses-Basel, v. 13, n. 11, NOV 2021. (16/00194-8, 18/14389-0, 18/13645-3, 17/26908-0, 20/02159-0, 17/13981-0, 19/09704-7, 18/10224-7, 19/24251-9, 20/04558-0)

SILVA-FILHO, JOAO LUIZ; DE OLIVEIRA, LILIAN G.; MONTEIRO, LETICIA; PARISE, PIERINA L.; ZANLUQUI, NAGELA G.; POLONIO, CAROLINA M.; DE FREITAS, CARLA L.; TOLEDO-TEIXEIRA, DANIEL A.; DE SOUZA, WILLIAM M.; BITTENCOURT, NAJARA; et al. Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice. BRAIN BEHAVIOR AND IMMUNITY, v. 97, p. 260-274, OCT 2021. (17/26908-0, 16/00194-8, 20/02159-0, 16/21259-0, 18/13866-0, 16/12855-9, 17/22062-9, 17/26170-0, 17/11828-0, 17/02402-0, 20/02448-2, 18/13645-3, 16/07371-2)

AMORIM, MARIENE R.; SOUZA, WILLIAM M.; BARROS, JR., ANTONIO C. G.; TOLEDO-TEIXEIRA, DANIEL A.; BISPO-DOS-SANTOS, KARINA; SIMEONI, CAMILA L.; PARISE, PIERINA L.; VIEIRA, ALINE; FORATO, JULIA; CLARO, INGRA M.; et al. Respiratory Viral Shedding in Healthcare Workers Reinfected with SARS-CoV-2, Brazil, 2020. Emerging Infectious Diseases, v. 27, n. 6, p. 1737-1740, JUN 2021. (20/04558-0, 16/00194-8, 20/02448-2, 18/14389-0, 17/13981-0, 17/26908-0, 19/24251-9, 20/02159-0)