Natural and semisynthetic diterpenoids with antiviral and immunomodulatory activities block the ERK signaling pathway

Abstract

The pathogenesis of many viral infections lies on the damage caused by the immune response against the virus. Current antiviral drugs do not act on the inflammatory component of the disease. Thus, new compounds that inhibit both viral multiplication and the immunopathology elicited by the virus are an approach that should be considered. In the present study, we identified two jatropholones (2A and 5B) and one carnosic acid derivative (9C) that significantly inhibited multiplication of TK+ and TK- strains of HSV-1 in Vero cells. Compounds 2A, 5B and 9C also prevented HSV-1- and TLRs-induced inflammatory response in cultivated murine macrophages. In macrophages infected with HSV-1, the inhibitory effect of compounds 2A, 5B and 9C on TNF-α and IL-6 production could be associated with the block of ERK pathway, whereas NF-κB pathway was not hampered by any of the compounds. Besides, 2A, 5B and 9C also inhibited ERK pathway and reduced TNF-α production in macrophages stimulated with TLR2, TLR4 or TLR9 agonists and were able to hinder IL-6 secretion after activation with TLR2 or TLR4, but not with TLR9. The immunomodulatory effect of 2A, 5B and 9C in macrophages infected with HSV-1 may be a consequence of the inhibition of ERK pathway activated by TLRs. The availability of compounds with both antiviral and immunomodulatory properties which affect TLR signaling pathways might be a useful strategy to control the progress of virus-induced disease.

Virucidal, antiviral and immunomodulatory activities of β-escin and Aesculus hippocastanum extract

“…Then, J774A.1 cells were transfected with the NF-jB-LUC reporter vector and, 24 h later, infected with HSV-1 and treated with b-escin (5 lg/ml) and AH (20 lg/ml) for 8 h. We found that b-escin and AH did not induce NF-jB and AP-1 activation in uninfected cells. We verified that HSV-1 induced a strong NF-jB and AP-1 activation as previously reported, [9] and that, interestingly, both pathways were strongly inhibited by b-escin and AH in HSV-1 in J774A.1 HSV-1-infected cells (Figure 5a). We next determined whether the NF-jB and AP-1 pathways were affected by b-escin (5 lg/ml) and AH (20 lg/ml) in macrophages stimulated with different TLRs ligands during 8 h. Stimulation with TLRs ligands activated NF-jB and AP-1 pathways, whereas b-escin and AH prevented TLRs induced NF-jB and AP-1 activation (Figure 6a).…”

“…Thus, considering the rise of the resistant viruses against the current antivirals and the adverse effect of corticoids, there is a need to search for new potential anti‐HSV agents that act with different mechanisms. In this sense, the finding of novel compounds that inhibit both viral multiplication and the immunopathology triggered by the virus is an interesting approach that is being considered …”

“…In this sense, the finding of novel compounds that inhibit both viral multiplication and the immunopathology triggered by the virus is an interesting approach that is being considered. [9,10] Medicinal plants have been used to treat viral infections for decades. In fact, in the last years, plant extracts and herbal compounds have been investigated for their anti-HSV and immune regulatory properties.…”

Imiquimod suppresses respiratory syncytial virus (RSV) replication via PKA pathway and reduces RSV induced-inflammation and viral load in mice lungs

“…To assess the effects of TLR stimulation on RSV infection, HEp-2 and A549 cells were infected with RSV A2 (moi = 1) and treated with different concentrations of Pam2CSK4 (TLR 2/6 agonist), poly(I:C)-HMW (TLR 3 agonist), LPS (TLR 4 agonist), imiquimod (IMQ, TLR 7 agonist), resiquimod (RSQ, TLR 7/8 agonist) or CpG ODN 2395 (TLR 9 agonist). These TLR agonists concentrations were chosen based on published data that demonstrate TLR stimulation in different cell types in vitro (Tissari et al, 2005;Kan et al, 2012;Bueno et al, 2015;Lucifora et al, 2018;Salinas et al, 2019). After 24 h, the amounts of infectious virus particles in the culture medium were decreased only by treatment with imiquimod, while the other TLR agonists did not affect viral replication at these concentrations tested (Fig.…”

Studies of Jatrogossone A as a Reactive Oxygen Species Inducer in Cancer Cellular Models

“…The jatrophane and lathyrane diterpenoids are unique classes of macrocyclic systems featuring a trans-bicyclo [10.3.0]pentadecane framework, typically including hydroxylated or other oxygenated substituents. Such natural products have demonstrated a wide variety of biological properties including P-glycoprotein modulation 7 and antiproliferative, 8 antimalarial, 9a anti-inflammatory, 10 and antiviral properties. 11 The main objective of the present work was to identify novel natural products as potential sources of anticancer agents, particularly for the treatment of drug-resistant cancers.…”