Peptidomimetics

Naturally occurring peptides are substrates of enzymes and ligands of receptors. Many peptides serve as neurotransmitters and hormones. Because they control a variety of physiological processes, they are also implicated in different diseases. For several reasons peptides are usually unsuitable as drugs, so many efforts in medicinal chemistry aim at the development of peptidomimetics with improved properties. In contrast with proteins most peptides of small to medium size - 30 to 

Because polypeptides are involved in many regulatory processes in the body, polypeptides and their analogues are natural drug candidates. Endogenous polypeptides tend to be very potent with strong binding. Therefore, a known polypeptide is essentially already a lead, and the entire lead discovery process can be skipped. 

Polypeptides, however, have one major problem—poor pharmacokinetics. Most successful drugs are administered orally and must either be absorbed in the stomach 

The two following Case Studies demonstrate some of the typical challenges associated with optimizing a peptide lead into an orally available drug. 

The half-life of captopril is short ( 3 hours). A drug with a short half-life requires more frequent dosing to maintain an effective concentration in the body. This can result in inadvertently missed doses. More important than the short half-life, some patients taking captopril report rashes and a lack of taste sensation (dysgeusia). 

In the search for effective ACE inhibitors, marketable drugs were successfully developed from a peptide lead. 

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Nucleosides, nucleotides, peptidomimetics, and reverse transcriptase inhibitors in HIV infection therapy 98CCC449. 

Design and synthesis of conformationally fixed amino acids, particularly those of heterocyclic series, as peptidomimetics 97T12789. 

Amides with N-heterocyclic fragments as peptidomimetic growth hormone sec-retagogues 98JMC3103. 

Vertex also put in clinical trial VX-765, another caspase-1 -specific, YVAD-derived peptidomimetic that is in vitro slightly more potent then pralnacasan (IC50 0.8 nM). Evaluation of VX-765 in a mouse model of oxazolone-induced dermatitis showed a dose-dependent (10-100 mg/kg) inhibition of ear inflammation. Consequently, VX-765 was enrolled in a 4-week phase Ila safety and pharmacokinetic study for psoriasis. However, Vertex has not communicated any results yet. 

Hypogonadotropic hypogonadism Gonadotropin-releasing hormone (GnRH) receptor GnRH peptidomimetic antagonist... 

Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that interfere with effector binding and thereby disrupt signal transduction. AP-22408 decreases bone resorption in animal studies and may be a promising drug to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Scheme 6 Synthesis of peptidomimetics containing the pyrrole ring...

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

Muller G (2000) Peptidomimetic SH2 Domain Antagonists for Targeting Signal Transduction. 211 17-59... 

Randolph JT, DeGoey DA (2004) Peptidomimetic inhibitors of HIV protease. Curr Top Med Chem 4 1079-1095... 

Tong L, Qian C, Massariol MJ, Deziel R, Yoakim C, Lagace L (1998) Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease. Nat Struct Biol 5 819-826... 

Peptoids are an archetypal and relatively conservative example of a peptidomimetic oligomer (Tab. 1.1). In fact, the sequence of atoms along the peptoid backbone is identical to that of peptides. However, peptoids differ from peptides in the marmer of side chain appendage. Specifically, the side chains of peptoid oligo-... 

Recently, there has been significant interest in peptidomimetic forms of Tat49 57, not only because of its membrane translocation activity, but as a means of treating HIV infection [1]. Several peptoids, similar in sequence to Tat49 57, have been synthesized with the intention of preventing the HlV-Tat/Tar interaction, and thus preventing HIV replication [24, 25, 30, 31]. However, only recently has this class of peptoids been applied to membrane translocation and dmg delivery applications. 

The ability of these peptidomimetic collagen-structures to adopt triple helices portends the development of highly stable biocompatible materials with collagenlike properties. For instance, it has been found that surface-immobilized (Gly-Pro-Meu)io-Gly-Pro-NH2 in its triple-helix conformation stimulated attachment and growth of epithelial cells and fibroblasts in vitro [77]. As a result, one can easily foresee future implementations of biostable collagen mimics such as these, in tissue engineering and for the fabrication of biomedical devices. 

Efforts to investigate the questions posed here will lead to more useful peptoid designs while simultaneously leading to a better fundamental understanding of molecular recognition and sequence/structure/function relationships in non-natural, sequence-specific peptidomimetic ohgomers. 

Patch, J.A. and Barron, A.E. Mimicry of bioactive peptides by non-natural, sequence-specific peptidomimetic oligomers. Curr. Opin. Chem. Biol. 2002, 6, 872-877. 

However, most natural peptides are composed of L-form a-amino acids and because of the ubiquitous prevalence of peptidases they have limited biostability, and consequently low bioavailability. Thus, a novel field of peptidomimetics has emerged in drug discovery, in attempts to design non-peptide compounds mimicking the pharmacophore and thus the activity of the original peptide. 

A range of 6-substituted 2-amino-e-caprolactams 66 has been synthesized by a sequence published by Robl et al. for investigating the generation of peptidomimetics. After Swern oxidation of the dipeptide 63, the corresponding... 

It is important to emphasize that this lattice database is highly idealized compared to real databases. Unlike the lattice database, real databases cannot be treated as thermodynamic ensembles of protein-ligand complexes equilibrated at room temperature [33,34]. Two of the more straightforward reasons are mentioned here. First, real databases are inherently biased toward strong binders (K < 10 pM), because weak binders are difficult to crystallize and of lesser interest. Second, as mentioned above, real databases are not composed of a representative selection of proteins and ligands, and their compositions are biased toward peptide and peptidomimetic inhibitors and certain protein superfamilies. In contrast, because only one protein and four ligand types are used, the lattice database should have representative ligand compositions. 

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