Characterizing the anti-HIV activity of papuamide A.
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.
Andjelic
Cynthia D
CD
University of Utah, Department of Pharmacology and Toxicology, 30 S. 2000 E. Rm.201, Salt Lake City, UT 84112, USA.
Planelles
Vicente
V
Barrows
Louis R
LR
D000818:Animals; D019380:Anti-HIV Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D047630:Depsipeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship; D013997:Time Factors; D053586:Virus Internalization / Q000187:drug effects*
D019380:Anti-HIV Agents; D047630:Depsipeptides; D015699:HIV Envelope Protein gp120; C474170:papuamide A; C474171:papuamide B