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

Santos, Igor Andrade; Pereira, Anna Karla dos Santos; Guevara-Vega, Marco; Paiva, Raphael Enoque Ferraz de; Sabino-Silva, Robinson; Bergamini, Fernando R.G.; Corbi, Pedro P.; Jardim, Ana Carolina Gomes

doi:10.1016/j.actatropica.2021.106300

Cited by 14 publications

(9 citation statements)

References 54 publications

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“…The prolonged exposure of cells to the compound can result in higher cytotoxicity 57 , reinforcing the importance of further studies of the ADME-Tox profile in animal models. Additionally, to the best of our knowledge, this is the first description of LabMol-309 as inhibitor of CHIKV replication, and its low EC 50 value is in similar level with other inhibitors reported to block CHIKV replication, emphasizing the antiviral potential of this compound 58 , 59 . In this context, the results obtained from the antiviral assays suggest that LabMol-309 is a potential molecule to be further optimized to reduce its cytotoxicity and increase the selectivity index in cell-based antiviral assays.…”

Section: Discussionsupporting

confidence: 73%

Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate

Freire

Basso

Mendes

et al. 2022

Sci Rep

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Chikungunya virus (CHIKV) is the causative agent of Chikungunya fever, an acute febrile and arthritogenic illness with no effective treatments available. The development of effective therapeutic strategies could be significantly accelerated with detailed knowledge of the molecular components behind CHIKV replication. However, drug discovery is hindered by our incomplete understanding of their main components. The RNA-dependent RNA-polymerase (nsP4-CHIKV) is considered the key enzyme of the CHIKV replication complex and a suitable target for antiviral therapy. Herein, the nsP4-CHIKV was extensively characterized through experimental and computational biophysical methods. In the search for new molecules against CHIKV, a compound designated LabMol-309 was identified as a strong ligand of the nsp4-CHIKV and mapped to bind to its active site. The antiviral activity of LabMol-309 was evaluated in cellular-based assays using a CHIKV replicon system and a reporter virus. In conclusion, this study highlights the biophysical features of nsP4-CHIKV and identifies a new compound as a promising antiviral agent against CHIKV infection.

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Section: Discussionsupporting

confidence: 73%

Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate

Freire

Basso

Mendes

et al. 2022

Sci Rep

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“…We also demonstrated that the peptide did not exert an inhibitory action on CHIKV entry into BHK-21 cells by protecting the cells against viral infection or by damaging the viral particle, since this peptide did not exhibit a virucidal effect and because pretreatment of the cells provided no protection against subsequent CHIKV infection. It is not easy to explain these findings, as most compounds with an inhibitory effect on viral entry act through two main mechanisms: (1) direct action on the viral structure, inactivating virions and thus preventing their interaction with the host cell and/or (2) interference with host cell components that are crucial to viral infection [ 27 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

The Dimeric Peptide (KKYRYHLKPF)2K Shows Broad-Spectrum Antiviral Activity by Inhibiting Different Steps of Chikungunya and Zika Virus Infection

Ayusso

Lima

Santos

et al. 2023

Viruses

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Chikungunya virus (CHIKV) and Zika virus (ZIKV) are important disease-causing agents worldwide. Currently, there are no antiviral drugs or vaccines approved to treat these viruses. However, peptides have shown great potential for new drug development. A recent study described (p-BthTX-I)2K [(KKYRYHLKPF)2K], a peptide derived from the Bothropstoxin-I toxin in the venom of the Bothrops jararacussu snake, showed antiviral activity against SARS-CoV-2. In this study, we assessed the activity of this peptide against CHIKV and ZIKV and its antiviral action in the different stages of the viral replication cycle in vitro. We observed that (p-BthTX-I)2K impaired CHIKV infection by interfering with the early steps of the viral replication cycle, reducing CHIKV entry into BHK-21 cells specifically by reducing both the attachment and internalization steps. (p-BthTX-I)2K also inhibited the ZIKV replicative cycle in Vero cells. The peptide protected the cells against ZIKV infection and decreased the levels of the viral RNA and the NS3 protein of this virus at viral post-entry steps. In conclusion, this study highlights the potential of the (p-BthTX-I)2K peptide to be a novel broad-spectrum antiviral candidate that targets different steps of the replication cycle of both CHIKV and ZIKV.

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“…To investigate whether the compound interacts with the double-stranded RNA (dsRNA), an experiment using the previously described protocol [ 43 , 44 ] was performed. Briefly, fifteen nanograms of the dsRNA were incubated with 50 µM of [Co III (L 1 ) 2 ]Cl at room temperature for 45 min and electrophoresed on a 1% agarose gel prior to analysis by densitometry.…”

Section: Methodsmentioning

confidence: 99%

Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4

et al. 2022

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Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease that can result in disability. Until now, there is no antiviral treatment against CHIKV, demonstrating that there is a need for development of new drugs. Studies have shown that thiosemicarbazones and their metal complexes possess biological activities, and their synthesis is simple, clean, versatile, and results in high yields. Here, we evaluated the mechanism of action (MOA) of a cobalt(III) thiosemicarbazone complex named [Co III (L 1 ) 2 ]Cl based on its in vitro potent antiviral activity against CHIKV previously evaluated (80% of inhibition on replication) . Furthermore, the complex has no toxicity in healthy cells, as confirmed by infecting BHK-21 cells with CHIKV- nanoluciferase in the presence of the compound, showing that [Co III (L 1 ) 2 ]Cl inhibited CHIKV infection with the selective index of 3.26. [Co III (L 1 ) 2 ]Cl presented a post-entry effect on viral replication, emphasized by the strong interaction of [Co III (L 1 ) 2 ]Cl with CHIKV non-structural protein 4 (nsP4) in the microscale thermophoresis assay, suggesting a potential mode of action of this compound against CHIKV. Moreover, in silico analyses by molecular docking demonstrated potential interaction of [Co III (L 1 ) 2 ]Cl with nsP4 through hydrogen bonds, hydrophobic and electrostatic interactions. The evaluation of ADME-Tox properties showed that [Co III (L 1 ) 2 ]Cl presents appropriate lipophilicity, good human intestinal absorption, and has no toxicological effect as irritant, mutagenic, reproductive, and tumorigenic side effects. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00775-022-01974-z.

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

Cited by 14 publications

References 54 publications

Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate

Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate

The Dimeric Peptide (KKYRYHLKPF)2K Shows Broad-Spectrum Antiviral Activity by Inhibiting Different Steps of Chikungunya and Zika Virus Infection

Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4

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