Orally Active Antiviral Tripeptide Glycyl-Prolyl-Glycinamide Is Activated by CD26 (Dipeptidyl Peptidase IV) before Transport across the Intestinal Epithelium

Hubatsch, Ina; Lazorova, Lucia; Vahlne, Anders; Artursson, Per

doi:10.1128/aac.49.3.1087-1092.2005

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…We have previously reported that the precursor molecule GPG‐NH 2 is metabolized in two steps into the active antiviral metabolite, αHGA. First, GPG‐NH 2 is metabolized to glycine‐amide (G‐NH 2 ) through the specific action of CD26/dipeptidyl‐peptidase IV [20–22]. G‐NH2 is, in turn, converted into αHGA, the actual antiviral compound through oxidation of its α‐carbon.…”

Section: Introductionmentioning

confidence: 99%

Anti-human immunodeficiency virus type 1 agent alpha-hydroxy glycineamide enters the target cells via a mechanism of passive diffusion

Youssefi

Vahlne

2014

Journal of Pharmacy and Pharmacology

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Section: Introductionmentioning

confidence: 99%

Anti-human immunodeficiency virus type 1 agent alpha-hydroxy glycineamide enters the target cells via a mechanism of passive diffusion

Youssefi

Vahlne

2014

Journal of Pharmacy and Pharmacology

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“…Shorter di‐ and tripeptides have been observed to have biological functions in the protection against oxidative stress and immune deficiency (i.e. GSH) or can have antiviral activity .…”

Section: Introductionmentioning

confidence: 99%

Two birds with one stone: Doing metabolomics with your proteomics kit

2013

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Proteomic research facilities and laboratories are facing increasing demands for the integration of biological data from multiple ‘-OMICS’ approaches. The aim to fully understand biological processes requires the integrated study of genomes, proteomes and metabolomes. While genomic and proteomic workflows are different, the study of the metabolome overlaps significantly with the latter, both in instrumentation and methodology. However, chemical diversity complicates an easy and direct access to the metabolome by mass spectrometry (MS). The present review provides an introduction into metabolomics workflows from the viewpoint of proteomic researchers. We compare the physicochemical properties of proteins and peptides with metabolites/small molecules to establish principle differences between these analyte classes based on human data. We highlight the implications this may have on sample preparation, separation, ionisation, detection and data analysis. We argue that a typical proteomic workflow (nLC-MS) can be exploited for the detection of a number of aliphatic and aromatic metabolites, including fatty acids, lipids, prostaglandins, di/tripeptides, steroids and vitamins, thereby providing a straightforward entry point for metabolomics-based studies. Limitations and requirements are discussed as well as extensions to the LC-MS workflow to expand the range of detectable molecular classes without investing in dedicated instrumentation such as GC-MS, CE-MS or NMR.

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“…One of the most promising novel approaches is to target maturation of new viruses by blocking the Gag protein processing, via direct interaction of the drug with the Gag molecule, rather than the proteinase. Examples of such an approach are the peptide glycyl-prolyl-glycine-amide [16] and the small molecule drug, bevirimat.…”

Section: Introductionmentioning

confidence: 99%

Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection

Martin

Salzwedel

Allaway

2008

Antivir Chem Chemother

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Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibition of the final rate-limiting step in Gag processing by bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1-3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination halflife of 58-80 h, supporting once-daily dosing. Animal studies suggest that elimination of bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with < 1% of the administered dose appearing in the urine. In responsive patients, bevirimat has demonstrated a robust dosedependent reduction in viral load (> 1.5 log10 copies/ml). Short-term administration (< or = 14 days) of bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of bevirimat are currently underway.

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Orally Active Antiviral Tripeptide Glycyl-Prolyl-Glycinamide Is Activated by CD26 (Dipeptidyl Peptidase IV) before Transport across the Intestinal Epithelium

Cited by 6 publications

References 24 publications

Anti-human immunodeficiency virus type 1 agent alpha-hydroxy glycineamide enters the target cells via a mechanism of passive diffusion

Anti-human immunodeficiency virus type 1 agent alpha-hydroxy glycineamide enters the target cells via a mechanism of passive diffusion

Two birds with one stone: Doing metabolomics with your proteomics kit

Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection

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