Screening peptidomimetics

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. 

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 concept of tweezer-like two-armed molecules was used to construct synthetic receptor molecules based on methylene sulfonamide peptidomimetics.11291 When screened for binding against an encoded tripeptide library, one of the synthetic receptors demonstrated a remarkable binding selectivity 11291 the synthetic receptor affinity could be further increased by varying the hinge part of the peptidomimetic molecule.11301... 

Design, Synthesis, Screening, and Decoding of Encoded One-Bead One-Compound Peptidomimetic and Small Molecule Combinatorial Libraries... 

On-Bead Screening of Encoded Peptidomimetic and Small Molecule Libraries... 

Screening of an Encoded Peptidomimetic Library with Streptavidin-Alkaline Phosphatase Conjugate... 

The Ugi four-component condensation (U-4CC) between an aldehyde, an amine, a carboxylic acid and an isocyanide allows the rapid preparation of a-aminoacyl amide derivatives. The Ugi Reaction products can exemplify a wide variety of substitution patterns, and constitute peptidomimetics that have potential pharmaceutical applications. This reaction is thus very important for generating compound libraries for screening purposes. 

The chapter by Kiely reviews the preparation of libraries as mixtures from 1995 to the present. The important areas which are reviewed are methods of preparation, means of identifying active compounds from the mixtures, and why one might wish to prepare mixtures. The chapter also includes the preparation of mixtures of non-peptide molecules, as well as peptidomimetic molecules, and even a few examples of peptides. Examples are presented where mixture synthesis and screening have been effective in identifying interesting biological leads. 

Chakraborty TK, Ghosh S, Jayaprakash S, Sugar amino acid based scaffolds-novel peptidomimetics and their potential in combinatorial synthesis, Chem. High Throughput Screen, (5) 373—87, 2002. 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

The identification of peptidomimetics through combinatorial chemistry and high-throughput screening may negate the need to address the challenge of biopharmaceutical drag delivery. 

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