ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments

Wu, Yu; Pons, Véronique; Goudet, Amélie; Panigai, Laetitia; Fischer, Annette; Herweg, Jo-Ana; Kali, Sabrina; Davey, Robert A.; Laporte, Jérôme; Bouclier, Céline; Yousfi, Rahima; Aubenque, Céline; Merer, Goulven; Gobbo, Emilie; Lopez, Roman; Gillet, Cynthia; Cojean, Sandrine; Popoff, Michel R.; Clayette, Pascal; Grand, Roger Le; Boulogne, Claire; Tordo, Noël; Lemichez, Emmanuel; Loiseau, Philippe M.; Rudel, Thomas; Sauvaire, D.; Cintrat, Jean‐Christophe; Gillet, Daniel; Barbier, Julien

doi:10.1038/s41598-017-15466-7

Cited by 17 publications

(42 citation statements)

References 48 publications

(64 reference statements)

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“…Outbreaks of emerging pathogens without licensed treatments and with microbial drug-resistance are major public health threats [1][2][3]. An emerging strategy in anti-infectious drug discovery is to look for therapies targeting host functions, which are exploited by pathogens for infection and/or growth in host cells [4][5][6][7][8][9][10][11][12][13]. The endo-lysosomal system is made of dynamic organelles (early endosomes, recycling endosomes, late endosomes and lysosomes) into which cargo molecules are internalized, transported, recycled or digested for cellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of endo‐lysosomal pathway and autophagic flux by broad‐spectrum antipathogen inhibitor ABMA

Boulogne

Carle

et al. 2020

The FEBS Journal

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The endo-lysosome system is involved in endocytosis, protein sorting and degradation as well as autophagy. Numerous toxins and pathogens exploit this system to enter host cells and exert their deleterious effects. Modulation of host endo-lysosome pathway may restrict multiple toxins intoxication as well as pathogen infection. ABMA, selected from a high-throughput screening against the cytotoxicity of ricin toxin, exhibits a broad-spectrum anti-toxin and anti-pathogen activity. Here, we show that ABMA selectively retains endocytosed protein and toxin to late endosomes, and thus delaying their intracellular trafficking. It also impairs the autophagic flux by excessive fusion of late endosomes and autophagosomes. Its exclusive action on late endosomes and corresponding consequences on the endo-lysosomal pathway and autophagic flux are distinct from known inhibitors such as bafilomycin A1, EGA or chloroquine. Hence, besides being a broad-spectrum inhibitor of endocytosed toxins and pathogens, ABMA may serve as a molecular tool to dissect endo-lysosome system-related cellular physiology and mechanisms of pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Regulation of endo‐lysosomal pathway and autophagic flux by broad‐spectrum antipathogen inhibitor ABMA

Boulogne

Carle

et al. 2020

The FEBS Journal

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“…It is current practice in drug discovery processes to pretreat cells with the compound before infection, in order to better monitor a positive effect. ABMA was tested for anti-HSV-2 activity with treatment administered from 5 h before infection to the end of the assays, as reported previously [ 15 ]. As shown in Figure 2 B and Table 1 , ABMA inhibited HSV-2-induced CPE in a dose-dependent manner with an EC 50 value of 1.66 μM and a maximum inhibition rate of 93.36% at 3.13 μM.…”

Section: Resultsmentioning

confidence: 99%

“…The lack of an available vaccine and the emergence of drug resistance highlight the importance of developing alternative antivirals against HSV-2 with distinct modes of action [ 10 ]. ABMA has been demonstrated previously to be active against several intracellular pathogens exploiting host–vesicle transport [ 15 ]. Here we demonstrated that ABMA is an effective inhibitor of HSV-2, in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The viruses trapped in endocytic vesicles can then be released to the host cytoplasm by fusion of the virus envelope with the vesicle membranes [ 44 ]. The inhibitory effect of ABMA on HSV-2 entry might be related to its effect on host–vesicle transport [ 15 ], which is involved in the endocytic entry pathway of HSV-2. Antivirals targeting early stage infection have attracted significant attention because reduced entry of viruses into cells translates to decreased replication and spread to other cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The small molecule ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine], was first identified from a cell-based high throughput screening, as an inhibitor of ricin, both in cell cultures and in mice, selectively acting on host-endosomal trafficking [ 15 ]. Subsequently, ABMA has been reported to be active against other infectious pathogens, including bacterial toxins (diphtheria toxin from Corynebacterium diphtheriae, lethal toxin from Bacillus anthracis , toxin B from Clostridium difficile and lethal toxin from Clostridium sordellii ), viruses ( Ebola virus , Rabies virus and Dengue-4 virus ), bacteria (Simkaniaceae and Chlamydiaceae) and Leishmania parasite [ 15 ]. Each of these pathogens relies on host–endosomal trafficking for pathogenicity, indicating that the inhibitory effect of ABMA is related to host–vesicle transport [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Antiviral Effects of ABMA against Herpes Simplex Virus Type 2 In Vitro and In Vivo

Dai

et al. 2018

Viruses

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Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 μM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment.

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Autophagy initiation triggers p150Glued–AP-2β interaction on the lysosomes and facilitates their transport

Tempes,

Bogusz,

Brzozowska

et al. 2024

Cell. Mol. Life Sci.

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The endocytic adaptor protein 2 (AP-2) complex binds dynactin as part of its noncanonical function, which is necessary for dynein-driven autophagosome transport along microtubules in neuronal axons. The absence of this AP-2-dependent transport causes neuronal morphology simplification and neurodegeneration. The mechanisms that lead to formation of the AP-2-dynactin complex have not been studied to date. However, the inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) enhances the transport of newly formed autophagosomes by influencing the biogenesis and protein interactions of Rab-interacting lysosomal protein (RILP), another dynein cargo adaptor. We tested effects of mTORC1 inhibition on interactions between the AP-2 and dynactin complexes, with a focus on their two essential subunits, AP-2β and p150Glued. We found that the mTORC1 inhibitor rapamycin enhanced p150Glued–AP-2β complex formation in both neurons and non-neuronal cells. Additional analysis revealed that the p150Glued–AP-2β interaction was indirect and required integrity of the dynactin complex. In non-neuronal cells rapamycin-driven enhancement of the p150Glued–AP-2β interaction also required the presence of cytoplasmic linker protein 170 (CLIP-170), the activation of autophagy, and an undisturbed endolysosomal system. The rapamycin-dependent p150Glued–AP-2β interaction occurred on lysosomal-associated membrane protein 1 (Lamp-1)-positive organelles but without the need for autolysosome formation. Rapamycin treatment also increased the acidification and number of acidic organelles and increased speed of the long-distance retrograde movement of Lamp-1-positive organelles. Altogether, our results indicate that autophagy regulates the p150Glued–AP-2β interaction, possibly to coordinate sufficient motor-adaptor complex availability for effective lysosome transport.

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ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments

Cited by 17 publications

References 48 publications

Regulation of endo‐lysosomal pathway and autophagic flux by broad‐spectrum antipathogen inhibitor ABMA

Regulation of endo‐lysosomal pathway and autophagic flux by broad‐spectrum antipathogen inhibitor ABMA

Antiviral Effects of ABMA against Herpes Simplex Virus Type 2 In Vitro and In Vivo

Autophagy initiation triggers p150Glued–AP-2β interaction on the lysosomes and facilitates their transport

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