Peptide Secondary Structure Mimetics Research Articles

Comprehensive Peptidomimetic Libraries Targeting Protein–Protein Interactions

Transient protein-protein interactions (PPIs) are essential components in cellular signaling pathways as well as in important processes such as viral infection, replication, and immune suppression. The unknown or uncharacterized PPIs involved in such interaction networks often represent compelling therapeutic targets for drug discovery. To date, however, the main strategies for discovery of small molecule modulators of PPIs are typically limited to structurally characterized targets. Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs, but few screening libraries of such mimetics are available to interrogate PPI targets. We initiated a program to prepare a comprehensive small molecule library designed to mimic the three major recognition motifs that mediate PPIs (α-helix, β-turn, and β-strand). Three libraries would be built around templates designed to mimic each such secondary structure and substituted with all triplet combinations of groups representing the 20 natural amino acid side chains. When combined, the three libraries would contain a member capable of mimicking the key interaction and recognition residues of most targetable PPIs. In this Account, we summarize the results of the design, synthesis, and validation of an 8000 member α-helix mimetic library and a 4200 member β-turn mimetic library. We expect that the screening of these libraries will not only provide lead structures against α-helix- or β-turn-mediated protein-protein or peptide-receptor interactions, even if the nature of the interaction is unknown, but also yield key insights into the recognition motif (α-helix or β-turn) and identify the key residues mediating the interaction. Consistent with this expectation, the screening of the libraries against p53/MDM2 and HIV-1 gp41 (α-helix mimetic library) or the opioid receptors (β-turn mimetic library) led to the discovery of library members expected to mimic the known endogenous ligands. These efforts led to the discovery of high-affinity α-helix mimetics (K(i) = 0.7 μM) against HIV-1 gp41 as well as high-affinity and selective β-turn mimetics (K(i) = 80 nM) against the κ-opioid receptor. The results suggest that the use of such comprehensive libraries of peptide secondary structure mimetics, built around effective molecular scaffolds, constitutes a powerful method of interrogating PPIs. These structures provide small molecule modulators of PPI networks for therapeutic target validation, lead compound discovery, and the identification of modulators of biological processes for further study.

ChemInform Abstract: Design and Synthesis of Novel Conformationally Restricted Peptide Secondary Structure Mimetics.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A New Tool in Peptide Engineering: A Photoswitchable Stilbene‐type β‐Hairpin Mimetic

Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogenous peptides with new physicochemical and pharmacological properties. The development, synthesis, photochemical investigation, and conformational analysis of a stilbene-type beta-hairpin mimetic capable of light-triggered conformational changes have been achieved. In addition to standard spectroscopic techniques (nuclear Overhauser effects, amide temperature coefficients, circular dichroism spectroscopy), the applicability of self-diffusion measurements (longitudinal eddy current delay pulsed-field gradient spin echo (LED-PGSE) NMR technique) in conformational studies of oligopeptides is demonstrated. The title compound shows photoisomerization of the stilbene chromophore, resulting in a change in solution conformation between an unfolded structure and a folded beta-hairpin.

Chemogenomics with Peptide Secondary Structure Mimetics

There is increasing evidence that redox regulation of transcription, particularly activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB), is important in inflammatory diseases. Human thioredoxin (TRX), a member of the oxidoreductase superfamily, was initially identified, as a factor which augments the production of interleukin-2 receptor alpha (IL-2R alpha) in human T-cell lymphotropic virus type 1 (HTLV-1) infected patient T-cells. Substrates for the redox activity of TRX bind the active site cleft in extended strand structure. The rapid generation of high numbers of peptide secondary structure mimetics through solid-phase synthesis is a key technology for the identification of pharmaceutical leads based on such protein-peptide interactions. In this manuscript, we describe a chemogenomic approach utilizing an extended strand templated library to develop small molecule inhibitors to validate oxidoreductase molecular targets in a murine asthma model.

Design, Synthesis, and Application of Peptide Secondary Structure Mimetics

AbstractFor Abstract see ChemInform Abstract in Full Text.

Design, synthesis, and application of peptide secondary structure mimetics.

The secondary structure peptidomimetic approach is a rational way to develop novel nonpeptide pharmaceutical agents based upon biologically significant proteinaceous leads. A part of this approach elaborated in this laboratory over the past ten years is reviewed along with the recent developments in this field.

ChemInform Abstract: A Merger of Rational Drug Design and Combinatorial Chemistry: Development and Application of Peptide Secondary Structure Mimetics

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A merger of rational drug design and combinatorial chemistry: development and application of peptide secondary structure mimetics.

Recent efforts toward the development of peptide secondary structure mimetics at Molecumetics Ltd. for the discoveries of new drug candidates utilizing combinatorial chemistry with solid phase synthesis are described.

Design and synthesis of novel conformationally restricted peptide secondary structure mimetics

[structure: see text] A facile synthesis of the novel conformationally restricted reverse turn mimetic is described. The key features are the preparation of the alpha-keto amide and tandem bicyclic ring formation.

Synthesis of Conformationally Restricted Mimetics of -Turns and Incorporation into Desmopressin, an Analogue of the Peptide Hormone Vasopressin

Peptide secondary structure mimetics should accurately imitate the desired backbone conformation, and synthetic routes to peptidomimetics should allow for flexible introduction of side chains with correct stereochemistry. Both criteria are met by the enantioselective approach presented here. Mimetics of inverse and classical γ-turns (1 and 2, respectively) were assembled from three types of building blocks, all of which can be prepared in a few steps from commercially available starting materials.

Synthesis of Conformationally Restricted Mimetics of γ-Turns and Incorporation into Desmopressin, an Analogue of the Peptide Hormone Vasopressin

Peptide secondary structure mimetics should accurately imitate the desired backbone conformation, and synthetic routes to peptidomimetics should allow for flexible introduction of side chains with correct stereochemistry. Both criteria are met by the enantioselective approach presented here. Mimetics of inverse and classical γ-turns (1 and 2, respectively) were assembled from three types of building blocks, all of which can be prepared in a few steps from commercially available starting materials.

Malic acid: A convenient precursor for the synthesis of peptide secondary structure mimetics

Syntheses of optically active ether-linked β-lactams and aza-proline analogues via 4-bromo-2-hydroxybutanoic acid esters derived from (S)- or (R)-malic acid are described. From these intermediates peptide secondary structure mimetics can be synthesized.

ChemInform Abstract: Peptide Secondary Structure Mimetics: Applications to Vaccines and Pharmaceuticals

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.