Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Liu, Fa¹  Stephen, Andrew G.²  Waheed, Abdul A.³  Freed, Eric O.³  Fisher, Robert J.²  Burke, Terrence R., Jr.¹ 

[1] Natl Canc Inst Frederick, Med Chem Lab, Ctr Canc Res, Natl Inst Hlth Frederick, Frederick, MD 21702 USA

[2] SAIC Frederick Inc, Prot Chem Lab, Adv Technol Program, NCI Frederick, Frederick, MD 21702 USA

[3] Natl Canc Inst Frederick, HIV Drug Resistance Program, Natl Inst Hlth Frederick, Frederick, MD 21702 USA

关键词: Macrocycle;    Ring-closing metathesis;    Peptide mimic;    Peptide;    Solid-phase synthesis;   

DOI  :  10.1016/j.bmcl.2009.10.105

来源: Elsevier

【 摘 要 】

HIV-1 viral budding involves binding of the viral Gag(p6) protein to the ubiquitin E2 variant domain of the human tumor susceptibility gene 101 protein (Tsg101). Recognition of p6 by Tsg101 is mediated in part by a proline-rich motif that contains the sequence 'Pro-Thr-Ala-Pro' ('PTAP'). Using the p6-derived 9-mer sequence 'PEPTAPPEE', we had previously improved peptide binding affinity by employing N-alkylglycine ('peptoid') residues. The current study applies ring-closing metathesis macrocyclization strategies to Tsg101-binding peptide-peptoid hybrids as an approach to stabilize binding conformations and to observe the effects of such macrocyclization on Tsg101-binding affinity and bioavailability. Published by Elsevier Ltd.

【 授权许可】

Free