Abstract:The design, synthesis, and evaluation of a series of catechol-based non-peptide peptidomimetics of the peptide hormone somatostatin have been achieved. These ligands comprise the simplest known non-peptide mimetics of the i + 1 and i + 2 positions of the somatostatin beta-turn. Incorporation of an additional side chain to include the i position of the beta-turn induces a selective 9-fold affinity enhancement at the sst2 receptor.
Many "new generation" peptidomimetics are designed to present amino acid side chains only; they do not have structural features that resemble peptide main chains. These types of molecules have frequently been presented in the literature as mimics of specific secondary structures. However, many "side-chain only" peptidomimetics do not rest in single conformational states, but exist in a limited number of freely interconverting forms. These different conformations may resemble different secondary structures, so referring to them as, for instance, turn- or helical-mimics understates the ways they could adapt to various binding situations. Sets of scaffolds that can be used to mimic aspects of nearly every secondary structure, i.e. universal peptidomimetics, can be constructed. These may assume a privileged place in library design, particularly in high throughput screening for pharmacological probes for which binding conformations, or even the target itself, is unknown at the time the library is designed (critical review, 101 references).
Many "new generation" peptidomimetics are designed to present amino acid side chains only; they do not have structural features that resemble peptide main chains. These types of molecules have frequently been presented in the literature as mimics of specific secondary structures. However, many "side-chain only" peptidomimetics do not rest in single conformational states, but exist in a limited number of freely interconverting forms. These different conformations may resemble different secondary structures, so referring to them as, for instance, turn- or helical-mimics understates the ways they could adapt to various binding situations. Sets of scaffolds that can be used to mimic aspects of nearly every secondary structure, i.e. universal peptidomimetics, can be constructed. These may assume a privileged place in library design, particularly in high throughput screening for pharmacological probes for which binding conformations, or even the target itself, is unknown at the time the library is designed (critical review, 101 references).
“…This approach is appealing because small molecules without polyamide backbones are more likely to be orally bioavailable and proteolytically stable. Early examples of this type of mimic were from Hirschmann and Smith, who designed β-turn analogues based on sugar, , steroid, or even catechol backbones. Similarly, Hamilton − and others − used biphenyl, terphenyl, ,,,,,− and related ,,,,,, scaffolds to mimic helices.…”
This paper concerns peptidomimetic scaffolds that can present side-chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analog local pairs of amino acids (including non-contiguous ones) in any secondary structure, ie they are universal peptidomimetics. To illustrate this concept we designed a set of four peptidomimetic scaffolds (1 -4). Libraries based on these were made bearing side-chains corresponding to many of the proteinderived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together peptidomimetics based on scaffolds 1 -4 can adopt conformations that resemble almost any combination of local amino acid side-chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) is outlined.
“…A close proximity of the d -Trp 8 side chain to that of Lys 9 , as indicated by a high field shift of the Lys C γ H 2 in the NMR spectra, was a requisite for high potency . Despite the successful clinical development of small cyclic SRIF analogs such as octreotide, lanreotide, and vapreotide, , extensive research toward nonpeptide analogs that are selective for each receptor subtype was carried out over the past decade. − The critical side chains of the Phe 7 -Trp 8 -Lys 9 sequence were displayed successfully on a variety of nonpeptide scaffolds 3 − 8 (Figure ). ,,− 1 Structure of octreotide and of various SRIF mimetics.…”
The synthesis and biological evaluation of four peptidomimetic analogs of somatostatin based on a constrained Trp residue, 3-amino-indolo[2,3-c]azepin-2-one (Aia), are reported. It is shown that dipeptidomimetics with a D-Aia-Lys sequence, functionalized with N- and C-terminal aromatic substituents, display a good selectivity for both sst4 and sst5. This study allowed us to identify a new highly potent sst5 agonist with good selectivity over the other receptors, except versus sst4.
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