Guanidine alkaloid analogs as inhibitors of HIV-1 Nef interactions with p53, actin, and p56lck.
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.
Olszewski
Allison
A
Department of Chemistry, University of California, Irvine, CA 92697-2025, USA.
Sato
Ken
K
Aron
Zachary D
ZD
Cohen
Frederick
F
Harris
Aleishia
A
McDougall
Brenda R
BR
Robinson
W Edward
WE
Overman
Larry E
LE
Weiss
Gregory A
GA
D000199:Actins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology; D002460:Cell Line; D002472:Cell Transformation, Viral; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015693:Gene Products, nef / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D019151:Peptide Library; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus
D000199:Actins; D000470:Alkaloids; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015693:Gene Products, nef; D019151:Peptide Library; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D054311:nef Gene Products, Human Immunodeficiency Virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019791:Guanidine