Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride

Jalily, Pouria H.; Eldstrom, Jodene; Miller, Scott C.; Kwan, Daniel; Tai, Sheldon; Chou, Doug T. H.; Niikura, Masahiro; Tietjen, Ian; Fedida, David

doi:10.1124/mol.115.102731

Cited by 14 publications

(21 citation statements)

References 36 publications

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“…Vpu is proposed by some groups to possess an ion channel (or viroporin) function, and both HMA and BIT-225 are reported to block Vpu-dependent ion currents (4,5,7). If true, SM111 would be anticipated to inhibit this Vpu activity, given its structural similarity to HMA and our previous evidence that SM111 is a potent inhibitor of the influenza A/M2 viroporin (36). Interestingly, Vpu I17 is proposed to project into the center of a pentameric Vpu pore domain (61).…”

Section: Discussionmentioning

confidence: 99%

“…1C). We previously identified SM111 as a potent inhibitor of the influenza A/M2 ion channel that also blocks in vitro replication of influenza A virus without obvious cytotoxicity (36). Here, we describe SM111's ability to inhibit in vitro HIV-1 replication, including that of drug-resistant strains, with substantially less toxicity than that of HMA or BIT-225 in both a T cell line and primary cells.…”

mentioning

confidence: 88%

“…HEK-293T cells were purchased commercially (Lenti-X 293T; Clontech Laboratories) and maintained in D10ϩ medium (Dulbecco's modified Eagle medium with 4.5 g/liter glucose and L-glutamine [Lonza] supplemented with 10% FCS, 100 U penicillin/ml, and 100 g streptomycin/ml [Sigma]). SM111, SM113, and BIT-225 were synthesized as reported previously (35,36). For each compound, a 100 mM stock solution was prepared in dimethyl sulfoxide (DMSO), aliquoted, and stored at Ϫ20°C until use.…”

Section: Methodsmentioning

confidence: 99%

“…As the acylguanidine moiety is common to HMA, BIT-225, and other reported antiviral compounds (4), and is thus presumably required for anti-HIV-1 activity, we also assessed C-(6-azepan-1-yl-pyridin-3-yl)-methylamine (SM113; Fig. 1D) for use as a control analogue in which SM111's acylguanidine was replaced with a primary amine (36).…”

Section: Sm111mentioning

confidence: 99%

“…Based on this, we synthesized SM111, which resembles HMA except for the removal of one ring nitrogen and the exocyclic amino group, along with the chloro atom ( Fig. 1C) (36). As the acylguanidine moiety is common to HMA, BIT-225, and other reported antiviral compounds (4), and is thus presumably required for anti-HIV-1 activity, we also assessed C-(6-azepan-1-yl-pyridin-3-yl)-methylamine (SM113; Fig.…”

Section: Sm111mentioning

confidence: 99%

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Novel Acylguanidine-Based Inhibitor of HIV-1

Moons

Tietjen

Miller

et al. 2016

J Virol

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The emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe a novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibits in vitro replication of HIV-1, including strains resistant to licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24Gag production was unaffected, but virion release (measured as extracellular p24Gag ) was reduced and virion infectivity was substantially impaired, suggesting that SM111 acts at a late stage of viral replication. SM111-mediated inhibition of HIV-1 was partially overcome by a Vpu I17R mutation alone or a Vpu W22* truncation in combination with Env N136Y. These mutations enhanced virion infectivity and Env expression on the surface of infected cells in the absence and presence of SM111 but also impaired Vpu's ability to downregulate CD4 and BST2/tetherin. Taken together, our results support acylguanidines as a class of HIV-1 inhibitors with a distinct mechanism of action compared to that of licensed antiretrovirals. Further research on SM111 and similar compounds may help to elucidate knowledge gaps related to Vpu's role in promoting viral egress and infectivity. T he development and scale-up of effective combination antiretroviral therapies have significantly reduced human immunodeficiency virus type 1 (HIV-1)-related morbidity and mortality globally (1); however, selection and transmission of drug-resistant HIV-1 strains remain a concern (2, 3). Thus, new antivirals that overcome drug resistance or act via novel mechanisms are needed. Acylguanidines are a broad class of antiviral compounds that target ion channels and other host and viral factors (4-8). Their anti-HIV-1 activity is exemplified by 5-(N,N-hexamethylene) amiloride (HMA; Fig. 1A) (5, 6), as well as N-(5-(1-methyl-1H-pyrazol-4-yl)naphthalene-2-carbonyl)guanidine (BIT-225; Fig. 1B) (7). HMA and BIT-225 inhibit HIV-1 replication in monocyte-derived macrophages at low micromolar concentrations (6, 7). Moreover, treatment of infected cells with these compounds results in reduced budding and release of viral particles without affecting intracellular viral protein production, suggesting that blockade occurs at a late stage of viral replication (5, 7). IMPORTANCE New inhibitors of HIV-1 replication may be useful as therapeutics to counteract drug resistance and as reagents to perform more detailed studies of viral pathogenesis. SM111 is a small molecule that blocks the replication of wild-type and drug-resistant HIV-1 strains by impairing viral release and substantially reducing virion infectivity, most likely through its ability to preventHMA and BIT-225 are both reported to target the HIV-1 accessory protein Vpu, an ϳ81-amino-acid transmembrane protein that is found in HIV-1 and some simian immunodeficiency virus (SIV) lineages and enhances viral replication through multiple mechanisms (...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Sm111mentioning

confidence: 99%

Section: Sm111mentioning

confidence: 99%

See 3 more Smart Citations

Novel Acylguanidine-Based Inhibitor of HIV-1

Moons

Tietjen

Miller

et al. 2016

J Virol

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Put a cork in it: Plugging the M2 viral ion channel to sink influenza

et al. 2020

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Highlights• The M2 protein of influenza A is a proton-gated proton channel that is required for viral replication • Current influenza strains are resistant to licensed M2 antivirals, so new therapies that target M2 are needed • The structure and function of M2, rise of drug resistance mutations, and current antiviral strategies are discussed AbstractThe ongoing threat of seasonal and pandemic influenza to human health requires antivirals that can effectively supplement existing vaccination strategies. The M2 protein of influenza A virus (IAV) is a proton-gated, proton-selective ion channel that is required for virus replication and is an established antiviral target. While licensed adamantane-based M2 antivirals have been historically used, M2 mutations that confer major adamantane resistance are now so prevalent in circulating virus strains that these drugs are no longer recommended. Here we review the current understanding of IAV M2 structure and function, mechanisms of inhibition, the rise of drug resistance mutations, and ongoing efforts to develop new antivirals that target resistant forms of M2.

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