Antiviral Effects of ABMA and DABMA against Influenza Virus In Vitro and In Vivo via Regulating the Endolysosomal Pathway and Autophagy

Abstract

Influenza virus is an acute and highly contagious respiratory pathogen that causes great concern to public health and for which there is a need for extensive drug discovery. The small chemical compound ABMA and its analog DABMA, containing an adamantane or a dimethyl-adamantane group, respectively, have been demonstrated to inhibit multiple toxins (diphtheria toxin, Clostridium difficile toxin B, Clostridium sordellii lethal toxin) and viruses (Ebola, rabies virus, HSV-2) by acting on the host’s vesicle trafficking. Here, we showed that ABMA and DABMA have antiviral effects against both amantadine-sensitive influenza virus subtypes (H1N1 and H3N2), amantadine-resistant subtypes (H3N2), and influenza B virus with EC50 values ranging from 2.83 to 7.36 µM (ABMA) and 1.82 to 6.73 µM (DABMA), respectively. ABMA and DABMA inhibited the replication of influenza virus genomic RNA and protein synthesis by interfering with the entry stage of the virus. Molecular docking evaluation together with activity against amantadine-resistant influenza virus strains suggested that ABMA and DABMA were not acting as M2 ion channel blockers. Subsequently, we found that early internalized H1N1 virions were retained in accumulated late endosome compartments after ABMA treatment. Additionally, ABMA disrupted the early stages of the H1N1 life cycle or viral RNA synthesis by interfering with autophagy. ABMA and DABMA protected mice from an intranasal H1N1 challenge with an improved survival rate of 67%. The present study suggests that ABMA and DABMA are potential antiviral leads for the development of a host-directed treatment against influenza virus infection.

C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus

“…Previous studies have shown that a host-directed prophylactic strategy endows antitoxin inhibitors with expanded efficacy against viruses ( Dai et al., 2018 ; Gillespie et al., 2013 ; Wu et al., 2017 ; Shtanko et al., 2018 ). During manuscript revision, the toxin inhibitor ABMA was shown to protect cells and mice against IAV H1N1 ( Liu et al., 2022 ). In pilot experiments, we found also that C910 protected male mice against IAV, but not female mice (data not shown).…”

Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum

“… 14 , 15 ABMA was shown to exhibit a broad-spectrum activity against intracellular toxins and pathogens. 16 , 17 , 18 Particularly, ABMA showed a substantial efficacy against different intracellular bacteria, such as Chlamydia or Simkania , or viruses, such as Ebola, Dengue-4, HSV-2, and influenza virus. As well, ABMA inhibits the development of the protozoan parasite L. infantum with an IC 50 at ∼7 μM on intramacrophage amastigotes, but with a weak selectivity index (SI) at 3.6.…”