Submit Papers Directly to PNAS via Track II Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: Editorial BoardLink: AboutLink: SubscribeLink: AdvertiseLink: ContactLink: Sitemap Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Published online on September 15, 2004, 10.1073/pnas.0406040101
PNAS | September 28, 2004 | vol. 101 | no. 39 | 14079-14084
OPEN ACCESS ARTICLE


This Article
Free via Open Access: OA
Right arrow OA Full Text
Right arrow Full Text (PDF)
Right arrow Supporting Figures
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Olszewski, A.
Right arrow Articles by Weiss, G. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Olszewski, A.
Right arrow Articles by Weiss, G. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg  
What's this?

 Previous Article  | Table of Contents |  Next Article 

BIOCHEMISTRY
Guanidine alkaloid analogs as inhibitors of HIV-1 Nef interactions with p53, actin, and p56lck

Allison Olszewski *, Ken Sato *, Zachary D. Aron *, Frederick Cohen *, Aleishia Harris {dagger}, Brenda R. McDougall {dagger}, W. Edward Robinson, Jr. {dagger}, Larry E. Overman *, and Gregory A. Weiss *, {ddagger}, §

Departments of *Chemistry, {ddagger}Molecular Biology and Biochemistry, and {dagger}Pathology, University of California, Irvine, CA 92697-2025

Contributed by Larry E. Overman, August 17, 2004

With current anti-HIV treatments targeting only 4 of the 15 HIV proteins, many potential viral vulnerabilities remain unexploited. We report small-molecule inhibitors of the HIV-1 protein Nef. In addition to expanding the anti-HIV arsenal, small-molecule inhibitors against untargeted HIV proteins could be used to dissect key events in the HIV lifecycle. Numerous incompletely characterized interactions between Nef and cellular ligands, for example, present a challenge to understanding molecular events during HIV progression to AIDS. Assays with phage-displayed Nef from HIVNL4-3 were used to identify a series of guanidine alkaloid-based inhibitors of Nef interactions with p53, actin, and p56lck. The guanidines, synthetic analogs of batzellidine and crambescidin natural products, inhibit the Nef–ligand interactions with IC50 values in the low micromolar range. In addition, sensitive in vivo assays for Nef inhibition are reported. Although compounds that are effective in vitro proved to be too cytotoxic for cellular assays, the reported Nef inhibitors provide proof-of-concept for disrupting a new HIV target and offer useful leads for drug development.

Author contributions: A.O., Z.D.A., L.E.O., and G.A.W. designed research; A.O., K.S., A.H., and B.R.M. performed research; Z.D.A., K.S., and F.C. contributed new reagents/analytic tools; A.O., W.E.R., L.E.O., and G.A.W. analyzed data; A.O., G.A.W., W.E.R., and L.E.O. wrote parts of the paper and edited the paper.

Freely available online through the PNAS open access option.

§ To whom correspondence should be addressed. E-mail: gweiss{at}uci.edu.

© 2004 by The National Academy of Sciences of the USA


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg    What's this?


This article has been cited by other articles in HighWire Press-hosted journals:


Home page
 J. Gen. Virol.Home page
K. E. Seaton and C. D. Smith
N-Myristoyltransferase isozymes exhibit differential specificity for human immunodeficiency virus type 1 Gag and Nef
J. Gen. Virol., January 1, 2008; 89(1): 288 - 296.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
Y. Zuo, T. Matsusaka, J. Zhong, J. Ma, L.-j. Ma, Z. Hanna, P. Jolicoeur, A. B. Fogo, and I. Ichikawa
HIV-1 Genes vpr and nef Synergistically Damage Podocytes, Leading to Glomerulosclerosis
J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2832 - 2843.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
E. Pauls, J. Senserrich, B. Clotet, and J. A. Este
Inhibition of HIV-1 replication by RNA interference of p53 expression
J. Leukoc. Biol., September 1, 2006; 80(3): 659 - 667.
[Abstract] [Full Text] [PDF]