Peptides peptidomimetics

Conformationally rigid cyclic a-amino acids in the design of peptidomimetics, peptide models, and bioactive compounds 04UK849. 

Alkene peptidomimetics, peptides, where an amide bond has been replaced to give E-alkene [M. M. Hahn et al., J. Chem. Soc. Commun. 1980, 234 M. Kranz, H. Kessler, Tetrahedron Lett. 1996, 37, 5359]. 

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-... 

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. 

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. 

Fragment screening by NMR was applied recently in the search of non-peptidic small molecule inhibitors. Two scaffolds (13) and (14), which bind the enzyme at the S1-S3 and the S2 binding site respectively, as shown by chemical shift perturbation, were linked together to yield competitive inhibitors such as (15) with micromolar IC50 values [158]. There have been no reports of non-peptidic inhibitors with potency and pharmacokinetics similar to the peptidic or peptidomimetic inhibitors described above. 

Y Wacher, JA Silverman, Y Zhang, LZ Benet. Role of -glycoprotein and cytochrome P4503A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 87 1322-1330, 1998. 

Direct thrombin inhibitors such as hirudin, Hirulog, the peptide aldehyde efegatran, and peptidomimetic compound argatroban have undergone clinical trials. Their application in the prevention and treatment of deep vein thrombosis contin-... 

High throughput methods have increased our capacity for appropriate candidate compounds selection and also for developing libraries of novel compounds from which such candidates can be selected. Chapter 7 discusses the use of solid-phase synthesis for the high throughput production of peptides and other small molecules. In addition, as discussed in Chapter 6 on peptidomimetics, the swift production of novel leads holds considerable promise for future discovery of novel therapeutic agents. 

With this information in hand, initial attempts to generate BACE inhibitors used the peptidic Swedish variant substrate as a starting point and substituted the scissile amide bond with a statine. For example, Sinha et al. (1999) synthesized a P10-P4 1 Swedish variant peptide with a statine moiety in place of the Pl-Pl scissile bond and showed that this peptidomimetic displayed an IC50 of 40 pM for inhibition of BACE. Optimization of this inhibitor was then performed by systematic replacement of amino acid side chains. Replacement of the PE Asp residue by Val reduced the IC50 for BACE inhibition to 30 nM this inhibitor is referred to here as Stat-Val. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Brodin, B., et al. Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter, PepTl. Pharmacol. Toxicol. 2002, 90, 285-296. 

Han, H. K., et al. CHO/hPEPTl cells overexpressing the human peptide transporter (hPEPTl) as an alternative in vitro model for peptidomimetic drugs. J. Pharm. Sci. 1999, 88, 347-350. 

Some drugs with low intrinsic permeability achieve acceptable oral bioavailability because they are substrates for uptake transporters, which normally function in nutrient uptake. The most prominent example is the peptide transporter, PepTl, which is active toward peptidomimetic antibiotics such as cephalexin, the antiviral agent valacyclovir [24] and other drugs. PepTl is natively expressed in Caco-2 cells, and adenovirus transduction has been used to increase PepTl expression levels [25]. However, the expression of PepTl was not polarized in this system and this expressed system appears to be of limited value as an improved screening model. PepTl has also been expressed in Chinese hamster ovary cells and a variety of other mammalian systems [26, 27]. 

The structures of the drugs used as a small test set for the model are listed in Table 17.1. Loperamide and asimadoline are P-gp substrates terfenadine and ebastine are compounds that are rapidly metabolized alprazolam, dobazam, di-and mono-hydroxy-L66858 [11] are benzodiazepines testosterone and corticosterone are hormones and cefadroxyl, cefaclor, cephalotin and cefmetazole are cephalosporins [12]. Finally, peptides 1 to 10 are peptidomimetic drugs [13]. 

---