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Characterizing the anti-HIV activity of papuamide A.

Andjelic CD, Planelles V, Barrows LR - Mar Drugs (2008)

Bottom Line: This inhibition of viral entry was determined to not be due to papuamide A binding to CD4 or HIV gp120, the two proteins involved in the cell-virus recognition and binding.Together, these results suggest a direct virucidal mechanism of HIV-1 inhibition by papuamide A.We also demonstrate here that the other papuamides (B-D) are able to inhibit viral entry indicating that the free amino moiety of 2,3-diaminobutanoic acid residue is not required for the virucidal activity.

View Article: PubMed Central - PubMed

Affiliation: University of Utah, Department of Pharmacology and Toxicology, 30 S. 2000 E. Rm.201, Salt Lake City, UT 84112, USA.

ABSTRACT
Papuamide A is representative of a class of marine derived cyclic depsipeptides, reported to have cytoprotective activity against HIV-1 in vitro. We show here that papuamide A acts as an entry inhibitor, preventing human immunodeficiency virus infection of host cells and that this inhibition is not specific to R5 or X4 tropic virus. This inhibition of viral entry was determined to not be due to papuamide A binding to CD4 or HIV gp120, the two proteins involved in the cell-virus recognition and binding. Furthermore, papuamide A was able to inhibit HIV pseudotype viruses expressing envelope glycoproteins from vesicular stomatitis virus or amphotropic murine leukemia virus indicating the mechanism of viral entry inhibition is not HIV-1 envelope glycoprotein specific. Time delayed addition studies with the pseudotyped viruses show that papuamide A inhibits viral infection only at the initial stage of the viral life cycle. Additionally, pretreatment studies revealed that the virus, and not the cell, is the target of papuamide A's action. Together, these results suggest a direct virucidal mechanism of HIV-1 inhibition by papuamide A. We also demonstrate here that the other papuamides (B-D) are able to inhibit viral entry indicating that the free amino moiety of 2,3-diaminobutanoic acid residue is not required for the virucidal activity.

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Related in: MedlinePlus

Surface plasmon resonance showed papuamide A did not interact with sCD4 and gp120. Graphs show the calculated expected binding response versus the observed binding response for papuamide A (Pap A) with sCD4, gp120 or positive control peptide binding.
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f3-md-06-00528: Surface plasmon resonance showed papuamide A did not interact with sCD4 and gp120. Graphs show the calculated expected binding response versus the observed binding response for papuamide A (Pap A) with sCD4, gp120 or positive control peptide binding.

Mentions: The lack of tropism specificity demonstrated above suggested that the chemokine co-receptors (CXCR4 and CCR5) and the co-receptor binding domain of gp120 are not the targets of papuamide A inhibition. However, the initial step of HIV entry, binding of gp120 to CD4, is thought to be similar regardless of viral tropism, therefore, the ability of papuamide A to interact with CD4 or gp120 was assessed. Successful biotinylation of papuamide A without a significant loss of activity was achieved (data not shown) and the biotinylated papuamide A was utilized to quantify binding of sCD4 or gp120 by surface plasmon resonance (SPR). Fig. 3 shows the observed binding response (response in RU measured by the instrument) versus the expected binding response (see formula and explanation below) for sCD4 and gp120 with papuamide A. SPR binding responses for both proteins were determined not to be significant because the observed response was 600 times lower than the calculated expected response for sCD4 at the maximum concentration tested, and the observed response for gp120 was 54 times lower than the calculated expected response at the maximum concentration tested. Papuamide A was shown to interact with a positive control binding peptide, as expected in this system.


Characterizing the anti-HIV activity of papuamide A.

Andjelic CD, Planelles V, Barrows LR - Mar Drugs (2008)

Surface plasmon resonance showed papuamide A did not interact with sCD4 and gp120. Graphs show the calculated expected binding response versus the observed binding response for papuamide A (Pap A) with sCD4, gp120 or positive control peptide binding.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2630844&req=5

f3-md-06-00528: Surface plasmon resonance showed papuamide A did not interact with sCD4 and gp120. Graphs show the calculated expected binding response versus the observed binding response for papuamide A (Pap A) with sCD4, gp120 or positive control peptide binding.
Mentions: The lack of tropism specificity demonstrated above suggested that the chemokine co-receptors (CXCR4 and CCR5) and the co-receptor binding domain of gp120 are not the targets of papuamide A inhibition. However, the initial step of HIV entry, binding of gp120 to CD4, is thought to be similar regardless of viral tropism, therefore, the ability of papuamide A to interact with CD4 or gp120 was assessed. Successful biotinylation of papuamide A without a significant loss of activity was achieved (data not shown) and the biotinylated papuamide A was utilized to quantify binding of sCD4 or gp120 by surface plasmon resonance (SPR). Fig. 3 shows the observed binding response (response in RU measured by the instrument) versus the expected binding response (see formula and explanation below) for sCD4 and gp120 with papuamide A. SPR binding responses for both proteins were determined not to be significant because the observed response was 600 times lower than the calculated expected response for sCD4 at the maximum concentration tested, and the observed response for gp120 was 54 times lower than the calculated expected response at the maximum concentration tested. Papuamide A was shown to interact with a positive control binding peptide, as expected in this system.

Bottom Line: This inhibition of viral entry was determined to not be due to papuamide A binding to CD4 or HIV gp120, the two proteins involved in the cell-virus recognition and binding.Together, these results suggest a direct virucidal mechanism of HIV-1 inhibition by papuamide A.We also demonstrate here that the other papuamides (B-D) are able to inhibit viral entry indicating that the free amino moiety of 2,3-diaminobutanoic acid residue is not required for the virucidal activity.

View Article: PubMed Central - PubMed

Affiliation: University of Utah, Department of Pharmacology and Toxicology, 30 S. 2000 E. Rm.201, Salt Lake City, UT 84112, USA.

ABSTRACT
Papuamide A is representative of a class of marine derived cyclic depsipeptides, reported to have cytoprotective activity against HIV-1 in vitro. We show here that papuamide A acts as an entry inhibitor, preventing human immunodeficiency virus infection of host cells and that this inhibition is not specific to R5 or X4 tropic virus. This inhibition of viral entry was determined to not be due to papuamide A binding to CD4 or HIV gp120, the two proteins involved in the cell-virus recognition and binding. Furthermore, papuamide A was able to inhibit HIV pseudotype viruses expressing envelope glycoproteins from vesicular stomatitis virus or amphotropic murine leukemia virus indicating the mechanism of viral entry inhibition is not HIV-1 envelope glycoprotein specific. Time delayed addition studies with the pseudotyped viruses show that papuamide A inhibits viral infection only at the initial stage of the viral life cycle. Additionally, pretreatment studies revealed that the virus, and not the cell, is the target of papuamide A's action. Together, these results suggest a direct virucidal mechanism of HIV-1 inhibition by papuamide A. We also demonstrate here that the other papuamides (B-D) are able to inhibit viral entry indicating that the free amino moiety of 2,3-diaminobutanoic acid residue is not required for the virucidal activity.

Show MeSH
Related in: MedlinePlus