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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

Time dependent inhibition of infection by controls C34 (233 nM) and AZT (3.7 μM). CEM-SS cells were infected with DHIV-3 pseudotype virus expressing an X4 tropic envelope (IIINL4) and treated with control drugs at the stated time points. DHIV-3 represents infected cells treated with vehicle. Data is graphed as average with range from duplicate determinations. Percent infection was significantly different (p < 0.05) between infected cells that were untreated and those treated (*), between 0 hour and other timepoint treatments (a), and between 1hour and 2 hour timepoint treatments (b).
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f5a-md-06-00528: Time dependent inhibition of infection by controls C34 (233 nM) and AZT (3.7 μM). CEM-SS cells were infected with DHIV-3 pseudotype virus expressing an X4 tropic envelope (IIINL4) and treated with control drugs at the stated time points. DHIV-3 represents infected cells treated with vehicle. Data is graphed as average with range from duplicate determinations. Percent infection was significantly different (p < 0.05) between infected cells that were untreated and those treated (*), between 0 hour and other timepoint treatments (a), and between 1hour and 2 hour timepoint treatments (b).

Mentions: The pseudotype virus assay described above is a single round infectivity assay that can detect inhibition of early viral life cycle events. To confirm the activity of papuamide A in the pseudotyped virus system was due to inhibition of the initial viral entry steps, time delayed addition studies were performed. Compounds which are active during the entry process of the viral life cycle show a strong time dependency in their effectiveness. This is illustrated in Fig. 5a with the controls C34, an inhibitor of fusion, and AZT, a reverse transcriptase inhibitor. C34 showed a significant decrease in effectiveness when addition was delayed by 1 hour, with an even greater loss of activity when addition was delayed 2 hours. The profile of AZT showed no difference in activity when added 1 hour after infection, and only a minor loss of activity when added 2 hours after infection. Papuamide A’s profile (Fig. 5b) was similar to that of C34, indicating the observed activity is at the initial stages of the viral life cycle. A similar loss of inhibition due to delayed addition was also observed for pseudotype virus expressing VSV envelope glycoprotein when compared to pseudotype virus expressing an HIV envelope glycoprotein (Fig. 5c).


Characterizing the anti-HIV activity of papuamide A.

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

Time dependent inhibition of infection by controls C34 (233 nM) and AZT (3.7 μM). CEM-SS cells were infected with DHIV-3 pseudotype virus expressing an X4 tropic envelope (IIINL4) and treated with control drugs at the stated time points. DHIV-3 represents infected cells treated with vehicle. Data is graphed as average with range from duplicate determinations. Percent infection was significantly different (p < 0.05) between infected cells that were untreated and those treated (*), between 0 hour and other timepoint treatments (a), and between 1hour and 2 hour timepoint treatments (b).
© Copyright Policy
Related In: Results  -  Collection

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

f5a-md-06-00528: Time dependent inhibition of infection by controls C34 (233 nM) and AZT (3.7 μM). CEM-SS cells were infected with DHIV-3 pseudotype virus expressing an X4 tropic envelope (IIINL4) and treated with control drugs at the stated time points. DHIV-3 represents infected cells treated with vehicle. Data is graphed as average with range from duplicate determinations. Percent infection was significantly different (p < 0.05) between infected cells that were untreated and those treated (*), between 0 hour and other timepoint treatments (a), and between 1hour and 2 hour timepoint treatments (b).
Mentions: The pseudotype virus assay described above is a single round infectivity assay that can detect inhibition of early viral life cycle events. To confirm the activity of papuamide A in the pseudotyped virus system was due to inhibition of the initial viral entry steps, time delayed addition studies were performed. Compounds which are active during the entry process of the viral life cycle show a strong time dependency in their effectiveness. This is illustrated in Fig. 5a with the controls C34, an inhibitor of fusion, and AZT, a reverse transcriptase inhibitor. C34 showed a significant decrease in effectiveness when addition was delayed by 1 hour, with an even greater loss of activity when addition was delayed 2 hours. The profile of AZT showed no difference in activity when added 1 hour after infection, and only a minor loss of activity when added 2 hours after infection. Papuamide A’s profile (Fig. 5b) was similar to that of C34, indicating the observed activity is at the initial stages of the viral life cycle. A similar loss of inhibition due to delayed addition was also observed for pseudotype virus expressing VSV envelope glycoprotein when compared to pseudotype virus expressing an HIV envelope glycoprotein (Fig. 5c).

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