Tripeptides from Synthetic Amino Acids Block the Tat-TAR Association and Slow Down HIV Spread in Cell Cultures

• Published in: Chembiochem : a European journal of chemical biology Vol. 8; no. 15; pp. 1850 - 1856
• Main Authors: Ludwig, Verena, Krebs, Andreas, Stoll, Michaela, Dietrich, Ursula, Ferner, Jan, Schwalbe, Harald, Scheffer, Ute, Dürner, Gerd, Göbel, Michael W.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 15.10.2007; WILEY‐VCH Verlag
• Subjects: Alkanes - chemistry; Alkanes - pharmacology; Amino Acids - chemistry; Amino Acids - pharmacology; antiviral agents; Arginine - analogs & derivatives; Arginine - pharmacology; Cells, Cultured; fluorescent probes; HeLa Cells; HIV; HIV - drug effects; HIV - growth & development; HIV Long Terminal Repeat - drug effects; HIV-1 - drug effects; HIV-1 - growth & development; HIV-2 - drug effects; HIV-2 - growth & development; Human immunodeficiency virus 1; Humans; Hydrocarbons, Aromatic - chemistry; Hydrocarbons, Aromatic - pharmacology; Ligands; Magnetic Resonance Spectroscopy; Models, Chemical; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Peptide Fragments - antagonists & inhibitors; peptidomimetics; Pyrimidines - chemistry; Pyrimidines - pharmacology; RNA recognition; RNA, Viral - chemistry; RNA, Viral - metabolism; tat Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200700232

Non‐natural amino acids with aromatic or heteroaromatic side chains were incorporated into tripeptides of the general structure Arg‐X‐Arg and tested as ligands of the HIV RNA element TAR. Some of these compounds could compete efficiently with the association of TAR and Tat and downregulated a TAR‐controlled reporter gene in HeLa cells. Peptide 7, which contains a 2‐pyrimidinyl‐alkyl chain, also inhibited the spread of HIV‐1 in cell cultures. NMR studies of 7 bound to HIV‐2‐TAR gave evidence for contacts in the bulge region. Unexpected peptide properties highlight the importance of structural diversity for ligand discovery. Peptide ligands for the TAR RNA of HIV can be constructed from synthetic α‐amino acids and D‐arginine. The resulting pyrimidine derivative 1 was shown by NMR to bind in the bulge site of TAR. Peptide 1 efficiently displaces Tat and blocks a Tat–TAR‐dependent reporter gene. Viral proliferation in cell cultures can be greatly reduced.