The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

Abstract

To complement traditional antivirals, natural compounds that act via host targets and present high barriers to resistance are of increasing interest. In the work reported here, we detected that homoharringtonine (HHT) presents effective antiviral activity. HHT completely inhibited infections of vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and porcine epidemic diarrhea virus (PEDV) at concentrations of 50, 100, and 500 nM in cell cultures, respectively. Treatment with HHT at doses of 0.05 or 0.2 mg/kg significantly reduced viral load and relieved severe symptoms in PEDV- or NDV-infected animals. HHT treatment, however, moderately inhibited avian influenza virus (AIV) infection, suggesting its potent antiviral action is restricted to a number of classes of RNA viruses. In this study, we also observed that HHT actively inhibited herpes simplex virus type 1 (HSV-1) replication with a 50% inhibitory concentration (IC50) of 139 nM; the treatment with HHT at 1000 nM led to reductions of three orders of magnitude. Moreover, HHT antagonized the phosphorylation level of endogenous and exogenous eukaryotic initiation factor 4E (p-eIF4E), which might regulate the selective translation of specific messenger RNA (mRNA). HHT provides a starting point for further progress toward the clinical development of broad-spectrum antivirals.

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

“…Omacetaxine, a semi-synthetic form of homoharringtonine, is approved by FDA for treatment of chronic myeloid leukemia. Homoharringtonine has also been reported to exhibit potent anti-viral activity against herpesviruses (varicella-zoster virus, herpes simplex virus-1, pseudorabies virus), coronaviruses (porcine epidemic diarrhea virus and murine hepatitis virus), rhabdoviruses (VSV and rabies virus), and other viruses (hepatitis B virus, Newcastle disease virus, and echovirus 1) (Dong et al, 2018;Andersen et al, 2019). Here, we observed homoharringtonine inhibits SARS-CoV-2 with EC 50 at 2.10 μM (Fig.…”

“…Homoharringtonine is a plant alkaloid derived from Cephalotoxus fortunei. It exhibits anti-tumor activity by binding to the ribosomal A site to inhibit protein translation, leading to rapid loss of short-lived proteins including Mcl-1 and c-Myc that promote the survival of leukemia cells (Dong et al, 2018;Lu and Wang, 2014). Omacetaxine, a semi-synthetic form of homoharringtonine, is approved by FDA for treatment of chronic myeloid leukemia.…”

Potential antiviral options against SARS-CoV-2 infection

“…Homoharringtonine is an anticancer drug which is indicated for treatment of chronic myeloid leukaemia. It also possesses antiviral activities against HBV, MERS-CoV, HSV-1, EV1, VZV and SARS-CoV-2 (Andersen et al, 2019;Cao et al, 2015;Choy et al, 2020;Dong et al, 2018;Kim and Song, 2019;Romero et al, 2007). Homoharringtonine binds to the 80S ribosome and inhibits viral protein synthesis by interfering with chain elongation (Dong et al, 2018).…”

Shedding Light on the Effect of Natural Anti-Herpesvirus Alkaloids on SARS-CoV-2: A Treatment Option for COVID-19

“…This drug is a protein synthesis inhibitor and was approved by the U.S. Food and Drug Administration (FDA) for curing chronic or accelerated phase chronic myeloid leukemia [12]. In previous preclinical investigations, this compound was reported with powerful antiviral activity against herpesviruses such as herpes simplex virus 1, pseudorabies virus, and varicella-zoster virus [13,14].…”