Universal Peptidomimetics

Abstract

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.

Synthesis of a Biologically Active Triazole‐Containing Analogue of Cystatin A Through Successive Peptidomimetic Alkyne–Azide Ligations

“…The triazole moiety is considered as an universal peptidomimetic group that can accommodate any peptide secondary structure. [9] The introduction of triazole amide surrogates (Y[Tz]) by a peptidomimetic ligation strategy requires peptides modified at their C and N termini with a-amino alkynes and a-azido acids, respectively. The latter building blocks can be easily prepared [11] and introduced into peptide fragments using standard peptide chemistry, and the synthesis of chiral a-amino alkynes can be achieved in a few steps [4b, 9] from the protected parent amino acids.…”

Synthesis and Anticancer Evaluation of Complex Unsaturated Isosteviol-Derived Triazole Conjugates

“…In order to overcome the obstacles of side products formation from standard TFA, SOCl 2 and DCCmediated conditions [21][22][23][24] for the dehydration reaction of derivatives 2a-f and their poor solubility in organic solvents such as CH 3 CN, THF and toluene, we explored mild heating of 2a-f in concentrated formic acid in absence of any additives that provided derivatives 3a-f with good yields (Table 1). No significant side products were observed under this optimized condition.…”

“…Since the triazole ring is considered to be a mimic of the amide unit [22,24], the novel derivatives 3a-f can be categorized as Michael-type acceptors. The Michael acceptors, also known as electrophilic compounds, are characterized as α,β-unsaturated compounds with electron-withdrawing substituents such as ketone, ester or amide units [23], which has been proven to attribute to their anticancer activities.…”

Exercises in Pyrrolidine Chemistry: Gram Scale Synthesis of a Pro–Pro Dipeptide Mimetic with a Polyproline Type II Helix Conformation

“…Thus, the search for suitable synthetic peptidomimetics [2] targeting such interactions has nowadays led to intensive research activities in many laboratories. [3] A class of prominent protein-protein interactions, which are well understood from a structural biology point of view, are the interactions of so-called proline-rich motif-recognizing domains (PRDs) with proteins containing proline-rich motifs (PRMs).…”

“…Abstract: A practical and scalable synthesis of a Fmoc-protected tricyclic dipeptide mimetic (6), that is, a 1,4-diaza-tricyclo-[8.3.0 3,7 ]-tridec-8-ene derivative resembling a rigidified di-lproline in a polyproline type II (PPII) helix conformation, was developed. The strategy is based on a Ru-catalyzed ring-closing metathesis of a dipeptide (4) prepared by PyBOP coupling of cis-5-vinylproline tert-butylester (2) and trans-N-Boc-3-vinylproline (rac-3) followed by chromatographic diastereomer separation.…”