Viral channel proteins in intracellular protein–protein communication: Vpu of HIV-1, E5 of HPV16 and p7 of HCV

Fischer, Wolfgang B.; Li, Lihua; Mahato, Dhani Ram; Wang, Yiting; Chen, Chin-Pei

doi:10.1016/j.bbamem.2013.08.017

Cited by 10 publications

(9 citation statements)

References 120 publications

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“…Currently, no licensed ARVs target the accessory proteins of HIV-1. Vpu is an 81–82 amino acid transmembrane protein that is found in HIV-1 and a subset of SIVs and enhances viral replication through multiple functions [ 10 , 11 ]. Specifically, Vpu augments virion release by downregulating CD4 and the host restriction factor BST2/CD317/tetherin, which otherwise captures mature virions at the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

et al. 2015

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The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world.

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Section: Introductionmentioning

confidence: 99%

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

et al. 2015

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“…Most notably, Vpu augments virion release by downregulating CD4 (12-15), whose presence on the cell surface would otherwise promote elimination of infected cells through antibody-dependent cellular cytotoxicity (16-18), as well as the host restriction factor tetherin (also known as BST2 or CD317), whose presence would otherwise capture mature virions at the cell surface (19)(20)(21)(22). Vpu is also reported to form cationselective ion channels (11,(23)(24)(25)(26)(27)(28)(29)(30); however, this property is controversial (31, 32), and its role in HIV-1 replication is unknown (11). Since acylguanidines can also act on host ion channels, host transporters, and viral polymerases (4, 8), additional antiviral mechanisms are possible.…”

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confidence: 99%

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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“…Viroporins are involved in many protein-protein interactions (PPIs) that may be also susceptible to therapeutic intervention [see recent reviews (Fischer et al 2014;Nieva and Carrasco 2015)]. Both intraviral and virus-host interactions, in the form of a myriad of perturbations, can provide important insights into the mechanisms involved in the viral infectious cycle.…”

Section: Protein-protein Interactions (Ppis) Involving Viroporinsmentioning

confidence: 99%

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

Torres

2018

Subcellular Biochemistry

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Viroporins are short polypeptides encoded by viruses. These small membrane proteins assemble into oligomers that can permeabilize cellular lipid bilayers, disrupting the physiology of the host to the advantage of the virus. Consequently, efforts during the last few decades have been focused towards the discovery of viroporin channel inhibitors, but in general these have not been successful to produce licensed drugs. Viroporins are also involved in viral pathogenesis by engaging in critical interactions with viral proteins, or disrupting normal host cellular pathways through coordinated interactions with host proteins. These protein-protein interactions (PPIs) may become alternative attractive drug targets for the development of antivirals. In this sense, while thus far most antiviral molecules have targeted viral proteins, focus is moving towards targeting host proteins that are essential for virus replication. In principle, this largely would overcome the problem of resistance, with the possibility of using repositioned existing drugs. The precise role of these PPIs, their strain- and host- specificities, and the structural determination of the complexes involved, are areas that will keep the fields of virology and structural biology occupied for years to come. In the present review, we provide an update of the efforts in the characterization of the main PPIs for most viroporins, as well as the role of viroporins in these PPIs interactions.

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Viral channel proteins in intracellular protein–protein communication: Vpu of HIV-1, E5 of HPV16 and p7 of HCV

Cited by 10 publications

References 120 publications

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

Novel Acylguanidine-Based Inhibitor of HIV-1

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

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