Banca de DEFESA: ERICA ERLANNY DA SILVA RODRIGUES

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : ERICA ERLANNY DA SILVA RODRIGUES
DATE: 31/01/2024
TIME: 13:00
LOCAL: SALA DE PÓS-GRADUAÇÃO - PPGQB
TITLE:

DESIGN , SYNTHESIS AND BIOLOGICAL EVALUATION OF COMPOUNDS PEPTIDOMIMETICS POTENTIALLY
ACTIVE AGAINST THE VIRUS CHIKUNGUNYA

 

KEY WORDS:

 

Viral proteases, Neglected tropical diseases, Antivirals, Peptidomimetics, CHIKV.

PAGES: 190
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SUMMARY:

The Chikungunya virus (CHIKV) is an arbovirus of the genus Alphavirus transmitted by mosquitoes of the genus Aedes sp. and Culex sp., responsible for causing Chikungunya fever (CHIKF) which leads to major economic and public health impacts. Throughout history, it appears that CHIKV infections are mainly associated with developing countries, being responsible for endemic and recurrent outbreaks. However, in recent decades, CHIKV has spread globally. In general, its clinical manifestations range from a self-limited feverish state to debilitating polyarthralgia, which has been responsible for significant impacts on the region's economy, since its symptoms can last for months or years. Thus, the lack of specific antiviral therapy for this virus characterizes an urgent and necessary demand. In this scenario, peptidomimetics stand out as a promising chemical class in the development of new drugs, since they have been reported as inhibitors of viral proteases, acting at submicromolar concentrations. In this sense, this work sought to develop new antiviral agents against CHIKV targeting viral processes and/or structures involved in the replication cycle. Thus, three series of tri-peptides formed by the amino acids glycine (Gly) and leucine (Leu) in 3 different combinations in P1, P2 and P3 were developed through solid phase synthesis using Rink amide resin. In total, 18 tri-peptides were obtained, of which 6 showed an effect against CHIKV (EC50 2.2-38 μM) with CC50 >200 μM. Highlightingly, the in vitro assays resulted in the discovery of the peptidomimetics PEP15 and PEP16, unprecedented in the literature, with the most promising antiviral effects of this work. Furthermore, flow cytometry showed a reduction in the cytopathic effect in Vero cells infected by CHIKV. Although in silico analyzes suggested that these peptides interacted with catalytic residues of the nsp2 protease, biological assays under the nsp2 protease resulted in weak inhibition (IC50 > 1mM). Time drug addiction assays was performed to determine at which stage of the viral cycle the tri-peptides act. Therefore, this work reports important information on the development of new peptidomimetics against the CHIKV virus, with valuable information on the structure-activity relationship of this class of substances.

COMMITTEE MEMBERS:
Externo(a) ao Programa - 2151027 - ALEXANDRE URBAN BORBELY - nullInterno(a) - 2089941 - DIMAS JOSE DA PAZ LIMA
Interno(a) - 3182336 - EDEILDO FERREIRA DA SILVA JUNIOR
Externo(a) ao Programa - 1612086 - ENIO JOSE BASSI - nullInterno(a) - 1820117 - ISIS MARTINS FIGUEIREDO
Presidente - 1369387 - JOAO XAVIER DE ARAUJO JUNIOR