Repurposing potential of rimantadine hydrochloride and development of a promising platinum(II)-rimantadine metallodrug for the treatment of Chikungunya virus infection

dc.contributor.authorSantos, Igor Andrade
dc.contributor.authorPereira, Anna Karla dos Santos
dc.contributor.authorGuevara-Vega, Marco
dc.contributor.authorde Paiva, Raphael Enoque Ferraz
dc.contributor.authorSabino-Silva, Robinson
dc.contributor.authorBergamini, Fernando R.G.
dc.contributor.authorCorbi, Pedro P.
dc.contributor.authorJardim, Ana Carolina G. [UNESP]
dc.contributor.institutionUniversidade Federal de Uberlândia (UFU)
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2022-04-28T19:48:58Z
dc.date.available2022-04-28T19:48:58Z
dc.date.issued2022-03-01
dc.description.abstractMost of the patients infected with Chikungunya virus (CHIKV) develop chronic manifestations characterized by pain and deformity in joints, impacting their quality of life. The aminoadamantanes, in their turn, have been exploited due to their biological activities, with amantadine and memantine recently described with anti-CHIKV activities. Here we evaluated the antiviral activity of rimantadine hydrochloride (rtdH), a well-known antiviral agent against influenza A, its platinum complex (Pt-rtd), and the precursor cis-[PtCl2(dmso)2], against CHIKV infection in vitro. The rtdH demonstrated significant antiviral activity in all stages of CHIKV replication (29% in pre-treatment; 57% in early stages of infection; 60% in post-entry stages). The Pt-rtd complex protected the cells against infection in 92%, inhibited 100% of viral entry, mainly by a virucidal effect, and impaired 60% of post-entry stages. Alternatively, cis-[PtCl2(dmso)2] impaired viral entry in 100% and post-entry steps in 60%, but had no effect in protecting cells when administered prior to CHIKV infection. Collectively, the obtained data demonstrated that rtdH and Pt-rtd significantly interfered in the early stages of CHIKV life cycle, with the strongest effect observed to Pt-rtd complex, which reduced up to 100% of CHIKV infection. Moreover, molecular docking analysis and infrared spectroscopy data (ATR-FTIR) suggest an interaction of Pt-rtd with CHIKV glycoproteins, potentially related to the mechanism of inhibition of viral entry by Pt-rtd. Through a migration retardation assay, it was also shown that Pt-rtd and cis-[PtCl2(dmso)2] interacted with the dsRNA in 87% and 100%, respectively. The obtained results highlight the repurposing potential of rtdH as an anti-CHIKV drug, as well as the synthesis of promising platinum(II) metallodrugs with potential application for the treatment of CHIKV infections. Importance Chikungunya fever is a disease that can result in persistent symptoms due to the chronic infection process. Infected patients can develop physical disability, resulting and high costs to the health system and significant impacts on the quality of life of affected individuals. Additionally, there are no licensed vaccines or antivirals against the Chikungunya virus (CHIKV) and the virus is easily transmitted due to the abundance of viable vectors in epidemic regions. In this context, our study highlights the repurposing potential of the commercial drug rimantadine hydrochloride (rtdH) as an antiviral agent for the treatment of CHIKV infections. Moreover, our data demonstrated that a platinum(II)-rimantadine metallodrug (Pt-rtd) poses as a potent anti-CHIKV molecule with potential application for the treatment of Chikungunya fever. Altogether, rtdH and Pt-rtd significantly interfered in the early stages of CHIKV life cycle, reducing up to 100% of CHIKV infection in vitro.en
dc.description.affiliationLaboratory of Virology Institute of Biomedical Sciences Federal University of Uberlândia, Uberlândia-MG
dc.description.affiliationInstitute of Chemistry University of Campinas-UNICAMP, Campinas-SP
dc.description.affiliationInnovation Center in Salivary Diagnostic and Nanotheranostics Department of Physiology Institute of Biomedical Sciences Federal University of Uberlandia
dc.description.affiliationDepartment of Fundamental Chemistry Institute of Chemistry University of São Paulo
dc.description.affiliationLaboratory of Synthesis of Bioinspired Molecules Institute of Chemistry Federal University of Uberlândia, Uberlândia-MG 34000-902
dc.description.affiliationInstitute of Biosciences Humanities and Exact Sciences (Ibilce) São Paulo State University (Unesp) Campus São José do Rio Preto
dc.description.affiliationUnespInstitute of Biosciences Humanities and Exact Sciences (Ibilce) São Paulo State University (Unesp) Campus São José do Rio Preto
dc.identifierhttp://dx.doi.org/10.1016/j.actatropica.2021.106300
dc.identifier.citationActa Tropica, v. 227.
dc.identifier.doi10.1016/j.actatropica.2021.106300
dc.identifier.issn1873-6254
dc.identifier.issn0001-706X
dc.identifier.scopus2-s2.0-85122255677
dc.identifier.urihttp://hdl.handle.net/11449/223165
dc.language.isoeng
dc.relation.ispartofActa Tropica
dc.sourceScopus
dc.subjectAntiviral
dc.subjectChikungunya virus
dc.subjectDrug Repurposing
dc.subjectPlatinum(II) metallodrugs
dc.subjectRimantadine
dc.titleRepurposing potential of rimantadine hydrochloride and development of a promising platinum(II)-rimantadine metallodrug for the treatment of Chikungunya virus infectionen
dc.typeArtigo

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