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

Proceedings of the National Academy of Sciences of the United States of America
Allison OlszewskiGregory A Weiss

Abstract

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 HIV(NL4-3) were used to identify a series of guanidine alkaloid-based inhibitors of Nef interactions with p53, actin, and p56(lck). The guanidines, synthetic analogs of batzellidine and crambescidin natural products, inhibit the Nef-ligand interactions with IC(50) 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.

References

Jun 1, 1989·Journal of Autoimmunity·V TsaiN J Zvaifler
Jan 26, 1995·The New England Journal of Medicine·F KirchhoffR C Desrosiers
May 26, 1999·Journal of Molecular Biology·M GeyerH R Kalbitzer
Jun 3, 2000·Organic Letters·F CohenS K Sakata
Sep 15, 2000·Advances in Pharmacology·A L GreenwayD A McPhee
Jul 21, 2001·EMBO Reports·M GeyerB M Peterlin
Oct 25, 2001·Journal of the American Chemical Society·F Cohen, L E Overman
Jan 4, 2003·Chembiochem : a European Journal of Chemical Biology·Sachdev S SidhuKurt Deshayes
Apr 2, 2003·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·R M Gulick
Aug 22, 2003·Proceedings of the National Academy of Sciences of the United States of America·Pin-Fang LinRichard Colonno
Oct 24, 2003·Proceedings of the National Academy of Sciences of the United States of America·F LiC T Wild
Jun 5, 2004·Bioorganic & Medicinal Chemistry Letters·Zachary D AronCarman Cuevas
Aug 31, 2004·Journal of Natural Products·Carole A BewleyLarry E Overman

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Citations

Feb 24, 2006·Journal of the American Chemical Society·Frederick Cohen, Larry E Overman
Sep 26, 2006·The Journal of Organic Chemistry·Bradley L Nilsson, Larry E Overman
Feb 13, 2007·Journal of Natural Products·Nadine C GassnerR Scott Lokey
Jul 28, 2005·Natural Product Reports·Roberto G S Berlinck, Miriam H Kossuga
Nov 23, 2007·Natural Product Reports·Neil DixonJason Micklefield
Apr 19, 2011·Proceedings of the National Academy of Sciences of the United States of America·Lauren E BrownJohn A Porco
Mar 3, 2010·Cellular and Molecular Life Sciences : CMLS·Tomaz Bratkovic
Nov 1, 2011·Journal of Molecular Biology·Rosemarie VithayathilGregory A Weiss
Jul 9, 2011·Protein Science : a Publication of the Protein Society·Juan E DiazGregory A Weiss
Dec 20, 2007·The Journal of General Virology·Kelly E Seaton, Charles D Smith
Aug 24, 2013·Expert Opinion on Therapeutic Targets·Wojciech Witkowski, Bruno Verhasselt
Aug 23, 2016·Journal of Biomolecular Structure & Dynamics·Deeksha PandeyNarayanan Latha
Apr 14, 2017·Bioorganic & Medicinal Chemistry·Yunlong ShiJoshua G Pierce
Aug 1, 2008·Bioorganic & Medicinal Chemistry Letters·Sudipta MajumdarGregory A Weiss
Feb 9, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Muhamad Alif Che Nordin, Sin-Yeang Teow
Sep 22, 2006·Journal of the American Society of Nephrology : JASN·Yiqin ZuoIekuni Ichikawa
Sep 15, 2005·Chemistry : a European Journal·Jun ShimokawaKazuo Nagasawa
Sep 29, 2009·Expert Opinion on Therapeutic Patents·Franciszek Saczewski, Łukasz Balewski
Sep 12, 2009·Journal of Natural Products·Rémi LavillePhilippe Amade
Feb 3, 2015·Organic Letters·Yunlong Shi, Joshua G Pierce
Sep 1, 2005·Journal of the American Chemical Society·Allison Olszewski, Gregory A Weiss

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