Peptidyl boronic acids

Richardson PG, Hideshima T, Anderson KC (2003) Bortezomib (Velcade), a peptidyl boronic acid which is a reversible (0.6 nM Ki) proteasome inhibitor is currently in use and approved for the treatment of multiple myeloma. In addition, there are numerous ongoing clinical trials on the use of this agent for treatment of other malignant diseases Cancer Control 10 361... 

Some of the serine and cysteine TSA moieties are shown in Fig. 15.29. Selective inhibition between these two classes of protease can be achieved easily. For example, trifluorom-ethylketones (61) and peptidyl boronic acids (62) do not efficiently inhibit cysteine proteases. However, selective inhibition of enzymes within each class can be very difficult. 

Porcine pancreatic elastase-t-peptidyl boronic acid FAST 51.78 57.80 75.43 P212121 2.0 Takahashi et al (1989)... 

Figure 13.5 Macrocycllc peptidyl boronic acids as potential chymotrypsin inhibitors.

Carboxypeptidase P Dipeptidyl peptidase TV Enterostatin, EDTA Diisopropylfluorophosphate, IV-peptidyl- O-acylhydroxyl-amines, boronic acid analogues of proline and alanine,... 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

Support for this concept is provided by H NMR studies which have identified a downfield resonance of the hydrogen-bonded proton in this pair at 18 ppm in ch3miotrypsinogen and chymotrypsin at low pH and at 14.9-15.5 ppm at high pH values.Similar resonances are seen in the a-lytic protease, in sub-tilisin, in adducts of serine proteases with boronic acids or peptidyl trifluoromethyl ketones, in alkylated derivative of the active site histidine, and in molecular complexes that mimic the Asp-His pair in the active sites of serine pro teases. 

A. Pal, sugar-binding boronic acids,ary of Peptidyl Bis (Boroxoles) as Oligosaccharide Receptors in Water Identification of a Receptor for the Tumor Marker TF-Antigen Disaccharide, Angew. Chem., Int. Ed., 2010, 49(8), 1492-1495. 

As described above, two new Cu-catalyzed desulfitative transformations have been discovered that can be used for the construction of peptidyl ketones from peptidic thiol esters and boronic acids. Under aerobic reaction conditions, S -acylthiosalicylamides are effective and efficient, although 2 equiv of the boronic acid are mechanistically required (Scheme 23.6). In comparison, 5 -acyl-2-mercaptoaryloximes function as MT mimics and can produce peptidyl ketones under anaerobic reaction conditions from only a single equivalent of boronic acid. The latter reaction is also efficient and general, but in its current design, it is only catalytically effective at elevated temperatures (>90 C). 

Bicker KL, Sun J, Lavigne JJ, Thompson PR (2011) Boronic acid functionalized peptidyl synthetic lectins combinatorial library design, peptide sequencing, and selective glycoprotein recognition. ACS Comb Sci 13 232-243... 

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