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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

Binding of phosphatidylserine alone in not sufficient enough to inhibit viral entry. Binding of phosphatidylserine by annexin V (AV) was assessed in the virion fusion assay against X4 (NL4-3) and R5 (NL(AD8)) tropic virus. Control represents uninfected cells and NL4-3 or NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio. Data is graphed as the mean ± standard error, n≥4. Response ratio was significantly different (p < 0.05) from control (*), or between HIV infected cells that were untreated or treated (a).
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f7a-md-06-00528: Binding of phosphatidylserine alone in not sufficient enough to inhibit viral entry. Binding of phosphatidylserine by annexin V (AV) was assessed in the virion fusion assay against X4 (NL4-3) and R5 (NL(AD8)) tropic virus. Control represents uninfected cells and NL4-3 or NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio. Data is graphed as the mean ± standard error, n≥4. Response ratio was significantly different (p < 0.05) from control (*), or between HIV infected cells that were untreated or treated (a).

Mentions: Papuamide A’s ability to bind to phosphatidylserine was observed using surface plasmon resonance. Twenty percent phosphatidylserine and 80% phosphatidylcholine (PC) vesicles were tested alongside 100% PC vesicles. The PS:PC vesicles exhibited binding to papuamide A while the 100% PC vesicles did not (data not shown). This indicates there is a preferential binding of papuamide A to phosphatidylserine. To determine if binding of PS alone was sufficient to inhibit viral entry, annexin V (AV) was tested in the virion based fusion assay. AV (tested at the concentrations similar to and higher than that shown to inhibit HIV infection) did not have any inhibitory effect on either X4 or R5 virus entry, while papuamide A remained active (Fig. 7a). In addition the effect of papuamide A was unchanged in the presence of AV when tested in the pseudotype assay (Fig. 7b). The results suggest that PS binding does not appear to be necessary for papuamide A to block entry.


Characterizing the anti-HIV activity of papuamide A.

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

Binding of phosphatidylserine alone in not sufficient enough to inhibit viral entry. Binding of phosphatidylserine by annexin V (AV) was assessed in the virion fusion assay against X4 (NL4-3) and R5 (NL(AD8)) tropic virus. Control represents uninfected cells and NL4-3 or NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio. Data is graphed as the mean ± standard error, n≥4. Response ratio was significantly different (p < 0.05) from control (*), or between HIV infected cells that were untreated or treated (a).
© Copyright Policy
Related In: Results  -  Collection

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

f7a-md-06-00528: Binding of phosphatidylserine alone in not sufficient enough to inhibit viral entry. Binding of phosphatidylserine by annexin V (AV) was assessed in the virion fusion assay against X4 (NL4-3) and R5 (NL(AD8)) tropic virus. Control represents uninfected cells and NL4-3 or NL(AD8) HIV represents untreated infected cells. Viral entry is reported as a fluorescence ratio. Data is graphed as the mean ± standard error, n≥4. Response ratio was significantly different (p < 0.05) from control (*), or between HIV infected cells that were untreated or treated (a).
Mentions: Papuamide A’s ability to bind to phosphatidylserine was observed using surface plasmon resonance. Twenty percent phosphatidylserine and 80% phosphatidylcholine (PC) vesicles were tested alongside 100% PC vesicles. The PS:PC vesicles exhibited binding to papuamide A while the 100% PC vesicles did not (data not shown). This indicates there is a preferential binding of papuamide A to phosphatidylserine. To determine if binding of PS alone was sufficient to inhibit viral entry, annexin V (AV) was tested in the virion based fusion assay. AV (tested at the concentrations similar to and higher than that shown to inhibit HIV infection) did not have any inhibitory effect on either X4 or R5 virus entry, while papuamide A remained active (Fig. 7a). In addition the effect of papuamide A was unchanged in the presence of AV when tested in the pseudotype assay (Fig. 7b). The results suggest that PS binding does not appear to be necessary for papuamide A to block entry.

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