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| Author(s): |
Karina Bispo dos Santos
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2022-12-07 |
| Examining board members: |
José Luiz Proença Módena;
Clarice Weis Arns;
Danielle Bruna Leal de Oliveira
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| Advisor: | José Luiz Proença Módena |
| Abstract | |
Infectious diseases are the fourth leading cause of death and disability in the world, characterizing as a serious threat to public health and global economy. In Brazil, despite the several arboviral epidemics that have emerged in recent years, cases of febrile illness associated with the arbovirus Oropouche Orthobunyavirus (OROV) continue to occur, mainly in the Amazon region. OROV entry into host cells is dependent on clathrin-mediated endocytosis (CME), a highly orchestrated process involving the activity of adapter protein-associated kinase 1 (AAK1) and cyclin-associated kinase G (GAK). So far, there is no approved treatment to combat Oropouche fever, and one of the difficulties encountered is the high genetic diversity among orthobunyaviruses, which makes the development of compounds with direct antiviral activity challenging. Given this context, the focus of this research was to evaluate the antiviral effect against OROV of compounds with host-targeted action, mainly AAK1 and GAK inhibitors in infected Vero cells. Seven compounds were analyzed and six showed antiviral activity. The best results were obtained with the inhibitor of both kinases, AAK1 and GAK, in the pre-treatment conditions and in the periods of 0h and 2h after the adsorption time. LP935509, a commercial compound with inhibitory activity on AAK1 and GAK, presented IC50= 13.20 µM, while the compounds SGC-GAK-N, SGC-AAK1-1 and SGC-AAK1-N presented IC50 of 90.58, 104.60 and 403 µM respectively. Chloroquine inhibited OROV only at high concentrations, with an IC50 of 4,611 µM, SGC-GAK-1 inhibited 1log10 of OROV at 2.5 µM, and ribavirin showed no antiviral activity at the concentrations tested. Thus, we believe that our results illustrate the role of AAK1 and GAK, clathrin-mediated endocytosis, and endosomal acidification for OROV internalization (AU) | |
| FAPESP's process: | 20/02159-0 - Antiviral activity of AAK1 inhibitors against Oropouche infection |
| Grantee: | Karina Bispo dos Santos |
| Support Opportunities: | Scholarships in Brazil - Master |