De novo design and synthesis of somatostatin non-peptide peptidomimetics utilizing .beta.-D-glucose as a novel scaffolding

Abstract

Non-peptide peptidomimetics of the peptide hormone somatostatin (SRIF) were designed and synthesized, utilizing fl-D-glUCOSe as a novel scaffolding. Such compounds resemble conventional peptide analogs in that they retain critical amino acid side chains but differ in that they are devoid of both the peptide backbone and amide surrogates. Structure-activity relationships resulting from systematic deletion or modification of the side chains of 4a were consistent with expectations, with the exception that analogs 8a and 8b, lacking an indole side chain, bound to the SRIF receptor. A possible explanation for this unexpected result and its potential implications are discussed. Unexpectedly we also found that the primary amino group of Lys9 is not required for SRIF receptor binding or activation. Taken together, the results reported herein, and those described elsewhere,lJ support the validity of the concept of non-peptide scaffolding and also demonstrate that non-peptidal peptidomimetics can provide unexpected biological information not previously available from natural ligands or their peptidal analogs.

Carbohydrates in peptide and protein design

“…Thus, the carbohydrate scaffold can display substituents to control distance and geometry between them. In this context, Hirschmann et al 9,12 and Nicoloau et al 13 described nonpeptidal peptidomimetics with novel scaffolding. Already in 1977, Walter 14 had suggested that backbone amide elements may not be required for receptor interaction and that a cyclic scaffold could be used.…”

“…Already in 1977, Walter 14 had suggested that backbone amide elements may not be required for receptor interaction and that a cyclic scaffold could be used. Scaffolding had been used and proven in the 1980s, when Hirschmann et al 9,12 and Nicoloau et al 13 described an approach to design of peptidomimetics, wherein the entire amide backbone of a -turn is replaced by novel scaffoldings devoid of amide bonds or isosteric replacements (described in more detail in the section Carbohydrates as Scaffolds in the Design of Nonpeptide Peptidomimetics of Somatostatin).…”

“…In the early 1990s Hirschmann and coworkers 9,12 and Nicoloau and coworkers 13 published a series of groundbreaking papers in which they described the use of -D-glucopyranosides as scaffolds in the design and synthesis of nonpeptidal peptidomimetics of the hormone somatostatin, which led to the discovery of a partial somatostatin agonist. This was one of the very first successful examples of de novo designed nonpeptidal peptidomimetics on a novel scaffold.…”

Somatostatin Analogs for Cancer Treatment and Diagnosis: An Overview

“…The elucidation of the 3-dimensional structures of receptor subtype-selective somatostatin agonists has aided and will considerably enhance the rational design of novel analogs including non-peptide compounds [135][136][137]. Development of potent non-peptide somatostatin analogs is important because they may display a good bioavailabilty [138] following oral administration.…”

Chemical ecology: a view from the pharmaceutical industry.

“…Specificity of a small molecule for an individual protein family member may be overlayed on a common scaffold by groups that provide specific binding interactions (hydrophobic bonds, salt bridges, hydrogen bonds, etc.). For example, scaffolds designed to interact with an important family of signal transducing molecules, G-protein-linked receptors, provide an approach to a novel set of potentially selective ligands (47) (Fig. 4).…”