Potential New Anti-Human Immunodeficiency Virus Type 1 Compounds Depress Virus Replication in Cultured Human Macrophages

Ewart, Gary; Nasr, Najla; Naif, Hassan M.; Cox, G B; Cunningham, Anthony L.; Gage, Peter W.

doi:10.1128/aac.48.6.2325-2330.2004

Cited by 50 publications

(56 citation statements)

References 18 publications

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“…Ewart et al (18) and Premkumar et al (44) have demonstrated that derivatives of amiloride could block the ion channels formed by human immunodeficiency virus (HIV) Vpu and hepatitis C virus (HCV) p7, respectively. These derivatives were also shown to inhibit HIV replication (17). It was suggested by Gazina et al (20) that the picornaviral transmembrane protein 2B could be the target for EIPA.…”

Section: Discussionmentioning

confidence: 98%

Entry of Feline Calicivirus Is Dependent on Clathrin-Mediated Endocytosis and Acidification in Endosomes

Stuart

Brown

2006

J Virol

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Feline calicivirus is a major causative agent of respiratory disease in cats. It is also one of the few cultivatable members of Caliciviridae. We have examined the entry process of feline calicivirus (FCV). An earlier study demonstrated that acidification in endosomes may be required. We have confirmed this observation and expanded upon it, demonstrating, using drugs to inhibit the various endocytic pathways and dominant-negative mutants, that FCV infects cells via clathrin-mediated endocytosis. We have also observed that FCV permeabilizes cell membranes early during infection to allow the coentry of toxins such as ␣-sarcin. Inhibitors of endosome acidification such as chloroquine and bafilomycin A1 blocked this permeabilization event, demonstrating that acidification is required for uncoating of the genome and access to the cytoplasm.

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Section: Discussionmentioning

confidence: 98%

Entry of Feline Calicivirus Is Dependent on Clathrin-Mediated Endocytosis and Acidification in Endosomes

Stuart

Brown

2006

J Virol

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“…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)(5)(6)(7)(8). Their anti-HIV-1 activity is exemplified by 5-(N,N-hexamethylene) amiloride (HMA; Fig.…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…Since acylguanidines can also act on host ion channels, host transporters, and viral polymerases (4,8), additional antiviral mechanisms are possible. Unfortunately, the high in vitro cytotoxicity of most acylguanidines with antiviral activity has precluded more detailed molecular and cellular studies (4)(5)(6). For example, while BIT-225 has shown promise in early clinical trials (33), it displays lower activity in T cell lines, where inhibitory concentrations frequently cause cell death (7,34,35).…”

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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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Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Langarizadeh

Abiri

Ghasemshirazi

et al. 2020

Biotech and App Biochem

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The importance of new effective treatment methodologies for human immunodeficiency virus (HIV) is undeniable for the medical society. Viral protein U (Vpu), one of the disparaged accessory proteins of HIV, is responsible for the dissemination of viral particles, and HIV mutants lacking Vpu protein have remarkably reduced pathogenicity. Here, we explored the marine natural products to find the leading structures which can potentially inhibit the activity of Vpu in silico. To fulfill this goal, we set up a virtual screening based on molecular docking to evaluate the binding capacity of different marine products to Vpu. For validation, we used molecular dynamics simulation and monitored the root mean square deviation value and binding interactions. The results were intriguing when we realized that the hit compounds (phlorotannins) had previously been identified as reverse transcriptase and HIV protease inhibitors. This research inaugurates a new road to combat HIV by multifaceted mode of action of these marine natural products without putting the normal cells in jeopardy (with their safe toxicological profile).

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Potential New Anti-Human Immunodeficiency Virus Type 1 Compounds Depress Virus Replication in Cultured Human Macrophages

Cited by 50 publications

References 18 publications

Entry of Feline Calicivirus Is Dependent on Clathrin-Mediated Endocytosis and Acidification in Endosomes

Entry of Feline Calicivirus Is Dependent on Clathrin-Mediated Endocytosis and Acidification in Endosomes

Novel Acylguanidine-Based Inhibitor of HIV-1

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

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