Síntese e avaliação biológica de compostos peptidomiméticos potencialmente ativos contra o vírus Chikungunya

Abstract

Chikungunya virus (CHIKV) is an arbovirus of the Alphavirus genus transmitted by mosquitoes of the 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-limiting febrile 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. 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. Given the above, this work seeks to develop new antiviral agents against CHIKV, acting through the inhibition of essential viral proteins during 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 in solid phase. In total, 18 tri-peptides were obtained, of which 6 showed an effect against CHIKV (EC50 2.2-38 µM) with CC50 >200 µM. Thus, this work resulted in the discovery of the peptidomimetics PEP15 and PEP16, unpublished in the literature, with the greatest antiviral effect in in vitro assays. Furthermore, a brief in silico analysis showed that PEP16 is able to interact with catalytic residues of the nsp2 protease. Thus, 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.