In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine

Loaiza-Cano, Vanessa; Monsalve-Escudero, Laura Milena; Restrepo, Manuel Pastrana; Quintero-Gil, Carolina; Pulido, Sergio; Galeano, Elkin; Zapata, Wildeman; Martínez-Gutiérrez, Marlen

doi:10.3390/molecules26113430

Cited by 4 publications

(2 citation statements)

References 66 publications

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“…Finally, we found that all concentrations evaluated significantly inhibited the viral protein production quantified by cell-ELISA (percentages of infection below 50%) ( Figure 1 C). 35 …”

Section: Resultsmentioning

confidence: 99%

Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids

et al. 2022

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Viral infections affect several million patients annually. Although hundreds of viruses are known to be pathogenic, only a few can be treated in the clinic with available antiviral drugs. Naturally based pharmacotherapy may be a proper alternative for treating viral diseases. Several natural and semisynthetic abietane-type diterpenoids have shown important antiviral activities. In this study, a biological evaluation of a number of either C-18- or C-19-functionalized known semisynthetic abietanes against Zika virus , Dengue virus , Herpes virus simplex type 1, and Chikungunya virus are reported. Semisynthetic abietane ferruginol and its analogue 18-(phthalimid-2-yl)ferruginol displayed broad-spectrum antiviral properties. The scale-up synthesis of this analogue has been optimized for further studies and development. This molecule displayed an EC 50 between 5.0 and 10.0 μM against Colombian Zika virus strains and EC 50 = 9.8 μM against Chikungunya virus. Knowing that this ferruginol analogue is also active against Dengue virus type 2 (EC 50 = 1.4 μM, DENV-2), we can conclude that this compound is a promising broad-spectrum antiviral agent paving the way for the development of novel antivirals.

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“…Finally, we found that all concentrations evaluated significantly inhibited the viral protein production quantified by cell-ELISA (percentages of infection below 50%) ( Figure 1 C). 35 …”

Section: Resultsmentioning

confidence: 99%

Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids

et al. 2022

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“…Previous studies have described the promotion of antiviral activity in DENV-2 when comparing a combined approach using a compound such as orlistat with individual approaches [ 46 ]. Similarly, in another flavivirus model (ZIKV/Col with derivatives of the amino acid L-tyrosine), the same result of improved inhibition via combined approaches compared with individual ones was observed [ 47 ].…”

Section: Discussionmentioning

confidence: 71%

The Antiviral and Virucidal Activities of Voacangine and Structural Analogs Extracted from Tabernaemontana cymosa Depend on the Dengue Virus Strain

Monsalve-Escudero

Loaiza-Cano

Zapata-Cardona

et al. 2021

Plants

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Currently, no specific licensed antiviral exists for treating the illness caused by dengue virus (DENV). Therefore, the search for compounds of natural origin with antiviral activity is an important area of research. In the present study, three compounds were isolated and identified from seeds of Tabernaemontana cymosa plants. The in vitro antiviral effect of those compounds and voacangine against different DENV strains was assessed using different experimental approaches: compounds added before the infection (Pre), at the same time with the virus (Trans), after the infection (Post) or compounds present in all moments of the experiment (Pre-Trans-Post, Combined treatment). In silico studies (docking and molecular dynamics) were also performed to explain the possible antiviral mechanisms. The identified compounds were three structural analogs of voacangine (voacangine-7-hydroxyindolenine, rupicoline and 3-oxo-voacangine). In the Pre-treatment, only voacangine-7-hydroxyindolenine and rupicoline inhibited the infection caused by the DENV-2/NG strain (16.4% and 29.6% infection, respectively). In the Trans-treatment approach, voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited the infection in both DENV-2/NG (11.2%, 80.4% and 75.7% infection, respectively) and DENV-2/16681 infection models (73.7%, 74.0% and 75.3% infection, respectively). The latter strain was also inhibited by 3-oxo-voacangine (82.8% infection). Moreover, voacangine (most effective virucidal agent) was also effective against one strain of DENV-1 (DENV-1/WestPac/74) and against the third strain of DENV-2 (DENV-2/S16803) (48.5% and 32.4% infection, respectively). Conversely, no inhibition was observed in the post-treatment approach. The last approach (combined) showed that voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited over 90% of infections (3.5%, 6.9% and 3.5% infection, respectively) of both strains (DENV-2/NG and DENV-2/16681). The free energy of binding obtained with an in silico approach was favorable for the E protein and compounds, which ranged between −5.1 and −6.3 kcal/mol. Finally, the complex formed between DENV-2 E protein and the best virucidal compound was stable for 50 ns. Our results show that the antiviral effect of indole alkaloids derived from T. cymose depends on the serotype and the virus strain.

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Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines

Monsalve-Escudero

Loaiza-Cano

Pájaro-González

et al. 2021

BMC Complement Med Ther

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Background In recent years, an increase in the occurrence of illnesses caused by two clinically- important arboviruses has been reported: Zika virus (ZIKV) and Chikungunya virus (CHIKV). There is no licensed antiviral treatment for either of the two abovementioned viruses. Bearing in mind that the antiviral effect of indole alkaloids has been reported for other arboviral models, the present study proposed to evaluate the antiviral in vitro and in silico effects of four indole alkaloids on infections by these two viruses in different cell lines. Methods The antiviral effects of voacangine (VOAC), voacangine-7-hydroxyindolenine (VOAC-OH), rupicoline and 3-oxo voacangine (OXO-VOAC) were evaluated in Vero, U937 and A549 cells using different experimental strategies (Pre, Trans, Post and combined treatment). Viral infection was quantified by different methodologies, including infectious viral particles by plating, viral genome by RT-qPCR, and viral protein by cell ELISA. Moreover, molecular docking was used to evaluate the possible interactions between structural and nonstructural viral proteins and the compounds. The results obtained from the antiviral strategies for each experimental condition were compared in all cases with the untreated controls. Statistically significant differences were identified using a parametric Student’s t-test. In all cases, p values below 0.05 (p < 0.05) were considered statistically significant. Results In the pre-treatment strategy in Vero cells, VOAC and VOAC-OH inhibited both viral models and OXO-VOAC inhibited only ZIKV; in U937 cells infected with CHIKV/Col, only VOAC-OH inhibited infection, but none of the compounds had activity in A549 cells; in U937 cells and A549 cells infected with ZIKV/Col, the three compounds that were effective in Vero cells also had antiviral activity. In the trans-treatment strategy, only VOAC-OH was virucidal against ZIKV/Col. In the post-treatment strategy, only rupicoline was effective in the CHIKV/Col model in Vero and A549 cells, whereas VOAC and VOAC-OH inhibited ZIKV infection in all three cell lines. In the combined strategy, VOAC, VOAC-OH and rupicoline inhibited CHIKV/Col and ZIKV/Col, but only rupicoline improved the antiviral effect of ZIKV/Col-infected cultures with respect to the individual strategies. Molecular docking showed that all the compounds had favorable binding energies with the structural proteins E2 and NSP2 (CHIKV) and E and NS5 (ZIKV). Conclusions The present study demonstrates that indole alkaloids are promising antiviral drugs in the process of ZIKV and CHIKV infection; however, the mechanisms of action evaluated in this study would indicate that the effect is different in each viral model and, in turn, dependent on the cell line.

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In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine

Cited by 4 publications

References 66 publications

Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids

Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids

The Antiviral and Virucidal Activities of Voacangine and Structural Analogs Extracted from Tabernaemontana cymosa Depend on the Dengue Virus Strain

Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines

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