Peptidomimetics—Tailored Enzyme Inhibitors

Abstract

Peptides and proteins (there is no clear boundary between the two classes of compounds) are absolutely essential components of organisms in many ways. While proteins have biocatalytic functions and are important components of tissues, peptides play an important role in the organism as hormones, neurotransmitters, and neuromodulators. Peptides and their analogues have long been used in medicinal chemistry as therapeutic agents for pathological conditions generally characterized by a disruption of the interplay between messenger molecules or enzyme substrates and their targets, the receptors and enzymes. For various biochemical and biophysical reasons there is an increasing tendency towards the use of chemical “Trojan horses” known as peptidomimetics. The chances that such agents are active generally increase with the magnitude of the “deceptive effect”, in other words in proportion to the degree of conversion of a peptide into a non‐peptide. Rational design has become a catchphrase which is at present applied frequently to the development of peptidomimetics. New computer programs are invaluable tools in such design processes. However, in spite of the many advances already made, we are still far from the final goal, the de novo design of peptidomimetics. Rational design is nonetheless advancing rapidly, and it is already clear that developments in the area of peptidomimetics have given a great boost to peptide chemistry as a whole. This can be expected to continue, so that in future peptide chemistry may be characterized by a type of symbiotic alliance between peptides and non‐peptides.

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

“…Tliis will ideally be a totally nonpeptidic compound that mimics the key structural properties of the complementary partner of the interaction by virtue of having appropriate functional groups oriented for interaction with the receptor (75)(76)(77)(78). Examples of published drug discovery programs which have embraced hierarchic, structure-based approaches broadly similar to those indicated above include studies on the somatostatin-opioid (79) and cyclophilin-cyclosporin (80) interactions and tiiimics of streptavidin (81), RGD (72,82,83), and EPO (84, 85) binding motifs.…”

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

“…Poly-N-substituted glycines (peptoids) comprise another class of peptidomimetics that differ from peptides only in that peptoid side chains are attached to the backbone amide nitrogen rather than to the ␣-carbon (27), making them protease-resistant (28). More than any of the other peptidomimetic systems under study (29), including ␤-peptides (26,30), ␤-peptoids (31), oligoureas (32), and oligo(phenylene ethynylene)s (33), peptoids (34)(35)(36) are particularly well suited for AMP mimicry because they are easily synthesized on solid phase (by using conventional peptide synthesis equipment) with access to diverse sequences at relatively low cost (27). Any chemical functionality available as a primary amine can be incorporated via a submonomer synthetic method (27); thus, peptoids are highly and finely tunable.…”

Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere

“…In this context, the area of peptidomimetics provides new dimensions to the field of molecular diversity and drug discovery (Giannis and Kolter, 1993;Gante, 1994;Adessi and Soto, 2002). In particular, the development of new leads for drug discovery has taken advantage of the use of unnatural amino acids in different fields of medicinal chemistry, for the development of peptidomimetics possessing high molecular diversity and the capability to generate high-ordered structures (Cole, 1994;Juaristi and Lopez-Ruiz, 1999;Trabocchi et al, 2005;Trabocchi et al, 2007).…”

“…In particular, the carbonyl group at position 3 of the dipeptide Gly-Asn is mimicked by the acetal moiety in the bicyclic molecule, thus acting as a transition-state analogue, which is fundamental for peptidomimeticbased enzyme inhibitors (Giannis and Kolter, 1993;Gante, 1994). The replacement of the amide nitrogen atom at position 4 of the dipeptide by an oxygen atom, allows the maintenance of an heteroatom at such position.…”