Abstract
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.
Highlights
Among the infections caused by viruses transmitted by arthropods, dengue fever is the most frequent, with approximately 50–100 million cases worldwide each year [1]
Considering the need to continue the search for specific antivirals against dengue virus (DENV) and the previous findings on the antiviral potential of compounds extracted from T. cymosa, this study aimed to assess the antiviral effect of other compounds extracted from this plant on infections by various strains of DENV-2 and other serotypes, as well as to explore in silico interactions that may contribute to understanding the possible mechanism of antiviral action
The results showed that VOAC had a virucidal effect against one DENV-1 strain (DENV-1/Westpac/74) and the third strain of DENV-2 (DENV-2/S16803), with 48.5% infection (1.31 × 109 PFU/mL compared with 2.71 × 109 PFU/mL in control without compounds) and 32.4% infection (p < 0.05) (2.38 × 1010 PFU/mL compared with 7.33 × 1010 PFU/mL in control without compounds), respectively
Summary
Among the infections caused by viruses transmitted by arthropods, dengue fever is the most frequent, with approximately 50–100 million cases worldwide each year [1]. This illness is caused by the dengue virus (DENV). The global incidence of DENV and, the sickness that it causes has increased during the last 40 years, in Latin America [1]. Vector surveillance and control measures were discontinued, and mosquitoes reappeared in large quantities, which in turn caused outbreaks in Latin America in the late 1970s and early 1980s [3]. The highest number of cases were reported in 2010, 2019, and 2013, with the outbreak in 2013 showing the highest number of cases of severe dengue fever [4]
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