7516-60-1Relevant articles and documents
A structurally guided dissection-then-evolution strategy for ligand optimization of smoothened receptor
Ye, Lintao,Ding, Kang,Zhao, Fei,Liu, Xiaoyan,Wu, Yiran,Liu, Yang,Xue, Dongxiang,Zhou, Fang,Zhang, Xianjun,Stevens, Raymond C.,Xu, Fei,Zhao, Suwen,Tao, Houchao
, p. 1332 - 1336 (2017)
We present herein a novel dissection-then-evolution strategy for ligand optimization. Using the co-crystal structure of the smoothened receptor (SMO) as a guide, we studied the modular contribution of LY2940680 by systematically silencing the specific interaction between the individual residue(s) and the fragment in the ligand. Following evolution by focusing on the benzoyl part finally yielded an improved ligand 21.
Leveraging a "catch-Release" Logic Gate Process for the Synthesis and Nonchromatographic Purification of Thioether- or Amine-Bridged Macrocyclic Peptides
Kheirabadi, Mahboubeh,Creech, Gardner S.,Qiao, Jennifer X.,Nirschl, David S.,Leahy, David K.,Boy, Kenneth M.,Carter, Percy H.,Eastgate, Martin D.
supporting information, p. 4323 - 4335 (2018/04/25)
Macrocyclic peptides containing N-alkylated amino acids have emerged as a promising therapeutic modality, capable of modulating protein-protein interactions and an intracellular delivery of hydrophilic payloads. While multichannel automated solid-phase peptide synthesis (SPPS) is a practical approach for peptide synthesis, the requirement for slow and inefficient chromatographic purification of the product peptides is a significant limitation to exploring these novel compounds. Herein, we invent a "catch-release" strategy for the nonchromatographic purification of macrocyclic peptides. A traceless catch process is enabled by the invention of a dual-functionalized N-terminal acetate analogue, which serves as a handle for capture onto a purification resin and as a leaving group for macrocyclization. Displacement by a C-terminal nucleophilic side chain thus releases the desired macrocycle from the purification resin. By design, this catch/release process is a logic test for the presence of the key components required for cyclization, thus removing impurities which lack the required functionality, such as common classes of peptide impurities, including hydrolysis fragments and truncated sequences. The method was shown to be highly effective with three libraries of macrocyclic peptides, containing macrocycles of 5-20 amino acids, with either thioether- or amine-based macrocyclic linkages; in this latter class, the reported method represents an enabling technology. In all cases, the catch-release protocol afforded significant enrichment of the target peptides purity, in many cases completely obviating the need for chromatography. Importantly, we have adapted this process for automation on a standard multichannel peptide synthesizer, achieving an efficient and completely integrated synthesis and purification platform for the preparation of these important molecules.
NON-CHROMATOGRAPHIC PURIFICATION OF MACROCYCLIC PEPTIDES BY A RESIN CATCH AND RELEASE
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Paragraph 0069; 0070, (2019/01/06)
The disclosure is directed to compounds and methods for preparing purified macrocyclic peptide using "catch-release" methods. These methods comprise reacting a free amino group of a resin-bound linear peptide with an azide- or alkyne-functionalized cap to form a resin-bound capped linear peptide having an azide- or alkyne-functionalized cap; cleaving said capped linear peptide from the resin to form a free capped linear peptide having an azide- or alkyne-functionalized cap; reacting the free capped linear peptide having an azide-functionalized cap with an alkyne-functionalized catch resin, or reacting the free capped linear peptide having an akynyl-functionalized cap with an azide functionalized catch resin, to form a catch-resin bound capped linear peptide; reacting the catch-resin bound capped linear peptide under conditions sufficient to effect macrocyclization of the linear peptide and release of the macrocyclic peptide from the catch resin.
