Peptidomimetic inhibitor

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

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. 

Application to peptidomimetic inhibitors of the human immunodeficiency virus type 1 protease, J. Med. Chem 39 705 (1996). 

The idea for macrocydic peptidomimetic inhibitors of PDF originated from the structure of the reverse hydroxamate BB-3497 that was reported by Clements et al. [73]. On this basis, Hu et al. [81] designed the cyclic compound 135, in which a nonyl group serves as the cross-linked Pi and P3 side chain, as depicted in Fig. 8. 

Frecer, V., Berti, F., Benedetti, F., Miertus, S. Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing -Phe Psi Pro- core and displaying favourable ADME-related properties. J. Mol. Graph. Model. 2008, 27, 376-87. 

In addition to fusion inhibitors, novel viral enzymes (e.g., integrase) are also being studied integrase inhibitors may constimte a new direction in antiviral therapy. Viral serine proteases have likewise been identified as attractive antiviral targets. Based upon crystallographic structural data, novel peptidomimetic inhibitors are being developed. 

The first applications of solid phase synthesis were to peptides, hence it is no surprise that there have been several reports of HRMAS studies of peptide systems attached to a support. One of the earliest reports of HRMAS in a supported sample was that of Wang-bound lysine, whose structure was determined by TOCSY and HMQC HRMAS NMR.38 More recently, HRMAS NMR has been used to identify several peptidomimetic inhibitors of hepatitis C virus NS3 protease while on the resin.79 However, it is perhaps a bit surprising that more has not been made of HRMAS in attacking problems of relevance to peptide synthesis, although most recent interest is moving that way. Combinatorial chemistry and solid phase organic chemistry has been a much more active area using HRMAS techniques. 

Stereo view of the peptidomimetic inhibitor Ro 31-8959 (saquinavir) bound to the active site of HIV PR. The distribution of the specificity subsites S and S is identical to that shown in Figure 2. Note the stacking interaction between the quinoline moiety and the PI side chain of phenylalanine. 

An interesting concept for designing specific HIV PR peptidomimetic inhibitors with internal two-fold symmetry was first formulated by John Erickson and his colleagues from Abbott Laboratories [28]. 

Recent communications from Bristol-Myers Squibb [14,15] describe peptidomimetic inhibitors (Figure 7) that were designed to bind thrombin with an N- to C-polypeptide chain sense opposite that of the substrate and form interactions similar to those made by the first three residues of hirudin ( 1, Thr2, Tyr3). In the x-ray crystal structure of BMS-183507 (K = 17.2 nM) with thrombin [15], the N terminus is facing the catalytic site while the methyl ester is... 

Wu T-P, Yee V, Tulinsky A, Chrusciel R, Nakanishi H, Shen R, Priebe C, Kahn M. The structure of a designed peptidomimetic inhibitor complex of oc-thrombin. Protein Engineering 1993 5 471-478. 

The recent discovery of peptidomimetic inhibitors of the serine protease TTP-II (tripeptidyl peptidase-II) further illustrates the peptide scaffold-based design approach [72]. Specifically, relative to a known TTP-... 

Benzodiazepin-l,4-dione 22 was a key intermediate for synthesis of a series of peptidomimetic inhibitors <2004BML3535>. The preparation of 22 starts by the reaction of the enolate of diazepine 20 with trisyl azide giving azide 21. Reduction of 21 under heterogeneous hydrogenation conditions gives amine 22 (Scheme 4). 

CGP 57813 is a peptidomimetic inhibitor of human HIV-1 protease. This lipophilic compound has been successfully entrapped in polylactic acid (PLA) and into pH-sensitive methacrylic acid copolymer particles (EUDRAGIT L 1 GO-55) [69], After the application of a film-coating, the plasma concentration was acceptable and reached similar levels as with injections of drug-loaded PLA carriers. To hinder the proteolytic degradation of a drug, two types of enteric-coated pellets were applied simultaneously. One contained the protease inhibitor coated... 

Liljebris et al. synthesized 2-[4-[(2amino)propyl]-2-(l(2)7/-tetrazol-5-yl)phenoxy]acetic acid 606, peptidomimetic inhibitors of protein tyrosine phosphatase IB <2002JME1785>. 

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