Andrographolide Prevents EV-D68 Replication by Inhibiting the Acidification of Virus-Containing Endocytic Vesicles

Abstract

Enterovirus D68 (EV-D68) has emerged as a significant respiratory pathogen that can cause severe respiratory disease and acute neurologic disease. At present, there are no approved antiviral agents or vaccines for EV-D68. In this study, we demonstrate that andrographolide (ADO), an active component of Andrographis paniculata, exerts substantial antiviral activity against EV-D68 infection. ADO treatment dramatically inhibited EV-D68 RNA replication (EC50 = 3.45 μM) and protein synthesis without producing significant cytotoxicity at virucidal concentrations. ADO-treated cells did not show any changes in host immune activation, EV-D68 attachment, or viral 5′ UTR activity. Using a pH-sensitive fluorescent indicator system for endocytosis in living cells, we found that ADO prevented the acidification of endocytic vesicles after receptor-mediated endocytosis. Finally, we showed that ADO inhibited the viral replication of circulating isolated EV-D68 strains. In summary, our results demonstrate that ADO suppresses EV-D68 replication by targeting the maturation of virus-containing endosomes of EV-D68. This mechanism represents a promising strategy for drug development.

A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19)

“…Andrographolide, the main active component isolated from the extract of the herb andrographis paniculata, has a wide range of biological activities including immunity regulation, anti-virus, anti-bacteria, antiparasite, anti-tumor, and anti-hyperglycemia [113,114]. Previous studies have shown that andrographolide has a broad spectrum of antiviral properties, which inhibits various virus infections including influenza A virus (IAV) [115], human immunodeficiency virus (HIV) [116], Chikungunya virus (CHIKV) [117], dengue virus (DENV) [118,119], and Enterovirus D68 (EV-D68) [120]. Atchara Paemanee et al suggested that andrographolide may exert broad-spectrum antiviral activity by interfering a variety of cellular pathways (including autophagy, unfolded protein response (UPR) pathway and oxidative stress, etc.).…”

Sialoglycovirology of Lectins: Sialyl Glycan Binding of Enveloped and Non-enveloped Viruses

“…Several strains listed in Table 2 of small (+)ssRNA-containing viruses, pico-rna-viruses, in the family Picornaviridae, including equine rhinitis A virus (ERAV) in the genus Aphthovirus; [84][85][86]; EMCV has a wide host range including humans [87]; and low-neurovirulent TMEV is a mouse pathogen that is able to cause a chronic demyelinating disease and is thus used for studies on human multiple sclerosis [88] as shown in Table 2. The viral capsid of the picornaviruses comprises three virion proteins (VP1, VP2, and VP3) that form the shell and one virion protein (VP4) lying on the inner surface of the virus particle as illustrated in Fig.…”

“…Typically, binding of the viral capsid proteins of picornaviruses to receptors triggers endocytosis. When the endosome becomes acidic, the viral capsids undergo conformational change and/or a protease is activated, resulting in channel formation that allows the viral genome to pass through the host cytosol [84,93], except for EMCV and poliovirus for which it remains unclear whether their genomes can directly penetrate through the plasma membrane due to no requirement of low pH for infection [93,94]. Information on which virus strains require Sia and which sialyl glycan structure is a determinant for viral attachment and infection is critical to understand virus tropism and pathogenesis for diagnosis and treatment, especially the design of a detection system and inhibitors targeting Sia-binding sites in viral lectins.…”

“…(4) It is important to realize that some states of different virus infections may cause the same disease (such as red eyes possibly caused by influenza A viruses, EV70, CAV24v, and HAdV-D). (5) While the entry pathway of Sia-binding enveloped viruses is direct fusion on the host plasma membrane or fusion with the endosomal membrane, the entry pathway of Sia-binding non-enveloped viruses is endocytosis that is followed by endosomal permeabilization/lysis as a result of proteolysis and/or capsid conformational change (picornaviruses [84], caliciviruses [109], reoviruses [111], and adenoviruses [131])/lipolysis (parvoviruses [146,148]) or that is followed by the ERAD pathway (polyomaviruses [166]), except for EMCV, which possibly has direct penetration of its genome through the plasma membrane. (6) Molecular and structural studies have indicated that Sia-binding sites are usually on the heads of viral lectins except for reovirus σ1 capsid protein of T3D strain carrying Sia-binding sites on its body.…”

Recent advances on the role of host factors during non-poliovirus enteroviral infections

“…The antiviral efficacy of pyrazolo[3,4-d]pyrimidines have also been evaluated against enteroviruses; CV-B3 and EV-A71 virus infections where they inhibited their infections but the exact mechanism was not established [181]. More recently, andrographolide has been reported to suppress EV-D68 replication targeting the viral maturation within the acidified endosomes [182]. World Health organization (WHO) recommended combination therapy has also been evaluated for possible antiviral development against enteroviruses [183].…”