INTRODUCTION: The Chikungunya virus (CHIKV) is an Alphavirus from the Togaviridae family whose main form of transmission is the bite of a vector mosquito, with emphasis on Aedes aegypti and Aedes albopictus [1,2]. Data from the Pan American Health Organization reported 213,561 cases of CHIKV in the first half of 2023 alone, with 281 deaths in 13 of the countries and territories of the Americas, with 98% of cases referring to Brazil [3]. Infections caused by this virus, in the acute phase, have symptoms characteristic of other arboviruses such as fever, myalgia, arthralgia, itching and headache [4]. The chronic phase, in turn, is reported by around 60% of patients, being characterized by persistent polyarthritis and/or polyarthralgia, in addition to being associated with several neurological problems such as encephalitis, meningoencephalitis, Guillain-Barré syndrome and congenital infections [5–8]. Despite the above, there is currently no approved effective therapy targeting the CHIKV virus [9]. Therefore, strategies aimed at developing medicines to address this problem are extremely important for society. In this sense, in silico studies identified a potential peptidomimetic inhibitor containing the Gly-Gly-Leu sequence targeting the CHIKV nsP2 protease [10]. Subsequently, Singh and collaborators highlighted the antiviral activity of this compound, in which it was possible to verify a non-competitive inhibition of CHIKV nsP2 with (IC50: 34 µM), as well as inhibition of viral replication at the cellular level [11]. These studies supported the creation of the present work, which proposed the synthesis and antiviral evaluation against CHIKV of new tri-peptides formed by the amino acids Leucine (Leu) and Glycine (Gly) in different positions (P1-P2-P3) and with rationally planned modifications in the N-terminal region, based on the addition of substituted benzoic acids. AIMS: This work aimed at the synthesis and evaluation against CHIKV of new peptidomimetics formed by the amino acids Leucine (Leu) and Glycine (Gly) in different positions (P1-P2-P3) and with rationally planned modifications in the N-terminal region, based on from the addition of substituted benzoic acids. METHODS: The synthesis of tri-peptides was carried out using the methodology adapted from Behnam and collaborators (2015), which consists of the synthesis of peptides through the F-moc strategy in solid phase, using the Rink-amide® resin as a polymeric support [12]. RESULT AND DISCUSSION: The solid phase methodology proved to be effective for obtaining peptidomimetics. These were obtained with a high degree of purity (above 98%) and variable yields between 20-82%. These were also subjected to analyzes to determine their physical-chemical characteristics, such as melting point, in general, the intervals were three degrees, which correlates with purity. Furthermore, these tri-peptides were characterized by Nuclear Magnetic Resonance (NMR) of hydrogen (1H) and carbon (13C), where it was possible to observe signs and displacements characteristic of their formation. Furthermore, cytotoxicity tests revealed that the peptidomimetics obtained do not have a toxic profile at a concentration of up to 200 ?M, in addition to viral inhibition of up to 74% and IC50 against CHIKV between 11.62 and 38.84 ?M. CONCLUSION: In this work, the synthesis, analysis of physical-chemical characteristics, structural characterization through Nuclear Magnetic Resonance (NMR) of hydrogen (¹H) and carbon thirteen (¹³C) and evaluation of the antiviral profile against CHIKV of new peptidomimetics were carried out. The peptides were properly isolated and obtained with a high degree of purity. These compounds then underwent biological tests, where it was possible to verify good toxicity, as they were not toxic at concentrations of up to 200 µM. Furthermore, these peptidomimetics showed viral activity of up to 74% and IC50 against CHIKV between 11.62 and 38.84 ?M. Therefore, it is inferred that this work has great social relevance, as it showed positive results regarding the viral inhibition of CHIKV and has as its perspective the development of a safe and effective therapy for this virus.
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Comissão Organizadora
Francisco Mendonça Junior
Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
Gerd Bruno da Rocha
Comissão Científica
Ricardo Olimpio de Moura
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