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Niclosamide potentiates TMEM16A and induces vasoconstriction.

ABSTRACT: The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering niclosamide as a TMEM16A inhibitor to treat diseases such as asthma, COPD, and hypertension. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation, shining light on developing specific TMEM16A modulators to treat human diseases.

SUBMITTER: Liang P

PROVIDER: S-EPMC10418162 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Niclosamide potentiates TMEM16A and induces vasoconstriction.

Liang Pengfei P Wan Yui Chun S YCS Yu Kuai K Hartzell H Criss HC Yang Huanghe H

bioRxiv : the preprint server for biology 20230802

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations p ...[more]

PMID: 37577682

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Project description:Niclosamide and benzbromarone have been described as inhibitors of the calcium activated chloride channel, TMEM16A, and on this basis have been considered and tested as clinical candidates for the treatment of airway diseases. However, both compounds have previously demonstrated activity on a range of additional biological targets and it is unclear from the literature to what extent any activity on TMEM16A may contribute to efficacy in these models of airway disease. The aim of the present study was therefore to examine the pharmacology and selectivity of these clinical candidates together with a structurally unrelated TMEM16A blocker, Ani9, in a range of functional assays to better appreciate the putative role of TMEM16A in the regulation of both epithelial ion transport and the development of an airway epithelial mucus secretory phenoptype. Benzbromarone and Ani9 both attenuated recombinant TMEM16A activity in patch clamp studies, whereas in contrast, niclosamide induced a paradoxical potentiation of the TMEM16A-mediated current. Niclosamide and benzbromarone were also demonstrated to attenuate receptor-dependent increases in intracellular Ca2+ levels ([Ca2+]i) which likely contributed to their concomitant attenuation of the Ca2+-stimulated short-circuit current responses of FRT-TMEM16A and primary human bronchial epithelial (HBE) cells. In contrast, Ani9 attenuated the Ca2+-stimulated short-circuit current responses of both cell systems without influencing [Ca2+]i which supports a true channel blocking mechanism for this compound. Additional studies using HBE cells revealed effects of both niclosamide and benzbromarone on global ion transport processes (absorptive and secretory) as well as signs of toxicity (elevated LDH levels, loss of transepithelial resistance) that were not shared by Ani9. Ani9 also failed to influence the IL-13 induced differentiation of HBE towards a goblet cell rich, mucus hypersecreting epithelium, whereas niclosamide and benzbromarone attenuated numbers of both goblet and multiciliated cells, that would be consistent with cellular toxicity. Together these data challenge the description of niclosamide as a TMEM16A blocker and illustrate a range of off-target effects of both niclosamide and benzbromarone which may contribute to the reported activity in models of airway function.

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Niclosamide potentiates TMEM16A and induces vasoconstriction.

Publications

Niclosamide potentiates TMEM16A and induces vasoconstriction.

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