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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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Papuamides B-D inhibit HIV entry. Papuamides A-D were tested at the stated concentrations against NL(AD8) virus in the virion based fusion assay. Control represents uninfected cells and NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio calculated from the amount of blue versus green fluorescence, normalized to control. Results graphed as the mean ± standard error, n≥4. Fluorescence ratio was significantly different (p < 0.05) from control (*) or from untreated HIV infected cells (a).
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f8-md-06-00528: Papuamides B-D inhibit HIV entry. Papuamides A-D were tested at the stated concentrations against NL(AD8) virus in the virion based fusion assay. Control represents uninfected cells and NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio calculated from the amount of blue versus green fluorescence, normalized to control. Results graphed as the mean ± standard error, n≥4. Fluorescence ratio was significantly different (p < 0.05) from control (*) or from untreated HIV infected cells (a).

Mentions: While we were limited by the amount of papuamides B-D available for testing, the ability of these analogs to inhibit HIV entry was determined. Papuamide B exhibited similar inhibition of viral entry, approximately 80% inhibition at 710 nM, when compared to papuamide A (Fig. 8). Papuamides C and D were less potent, inhibiting approximately 30% and 55%, respectively, at concentrations of 40 and 20 fold higher (Fig. 8). Furthermore, papuamides C and D effective concentrations were closer to their cytotoxic concentrations suggesting a narrower “therapeutic” window for these analogs in vitro (data not shown).


Characterizing the anti-HIV activity of papuamide A.

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

Papuamides B-D inhibit HIV entry. Papuamides A-D were tested at the stated concentrations against NL(AD8) virus in the virion based fusion assay. Control represents uninfected cells and NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio calculated from the amount of blue versus green fluorescence, normalized to control. Results graphed as the mean ± standard error, n≥4. Fluorescence ratio was significantly different (p < 0.05) from control (*) or from untreated HIV infected cells (a).
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Related In: Results  -  Collection

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

f8-md-06-00528: Papuamides B-D inhibit HIV entry. Papuamides A-D were tested at the stated concentrations against NL(AD8) virus in the virion based fusion assay. Control represents uninfected cells and NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio calculated from the amount of blue versus green fluorescence, normalized to control. Results graphed as the mean ± standard error, n≥4. Fluorescence ratio was significantly different (p < 0.05) from control (*) or from untreated HIV infected cells (a).
Mentions: While we were limited by the amount of papuamides B-D available for testing, the ability of these analogs to inhibit HIV entry was determined. Papuamide B exhibited similar inhibition of viral entry, approximately 80% inhibition at 710 nM, when compared to papuamide A (Fig. 8). Papuamides C and D were less potent, inhibiting approximately 30% and 55%, respectively, at concentrations of 40 and 20 fold higher (Fig. 8). Furthermore, papuamides C and D effective concentrations were closer to their cytotoxic concentrations suggesting a narrower “therapeutic” window for these analogs in vitro (data not shown).

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