Serine proteases selectivities

Katz, B. A. Finer-Moore, J. Mortezaei, R. Rich, D. H. Stroud, R. M. Episelection Novel K. approximately nanomolar inhibitors of serine proteases selected by binding or chemistry on an enzyme surface. Biochemistry 1995, 34, 8264-8280. 

Protein G. This vitamin K-dependent glycoproteia serine protease zymogen is produced ia the Hver. It is an anticoagulant with species specificity (19—21). Proteia C is activated to Proteia by thrombomodulin, a proteia that resides on the surface of endothefial cells, plus thrombin ia the presence of calcium. In its active form, Proteia selectively iaactivates, by proteolytic degradation. Factors V, Va, VIII, and Villa. In this reaction the efficiency of Proteia is enhanced by complex formation with free Proteia S. la additioa, Proteia activates tissue plasminogen activator, which... 

The first compound to find widespread use as an inhibitor of AEA breakdown was phenylmethylsulfone (PMSF) (25). This non-selective serine protease inhibitor has been found to act as an irreversible inhibitor of FAAH preventing AEA breakdown [41, 47], and is commonly added to binding... 

The starting point for much of the work described in this article is the idea that quinone methides (QMs) are the electrophilic species that are generated from ortho-hydro-xybenzyl halides during the relatively selective modification of tryptophan residues in proteins. Therefore, a series of suicide substrates (a subtype of mechanism-based inhibitors) that produce quinone or quinonimine methides (QIMs) have been designed to inhibit enzymes. The concept of mechanism-based inhibitors was very appealing and has been widely applied. The present review will be focused on the inhibition of mammalian serine proteases and bacterial serine (3-lactamases by suicide inhibitors. These very different classes of enzymes have however an analogous step in their catalytic mechanism, the formation of an acyl-enzyme intermediate. Several studies have examined the possible use of quinone or quinonimine methides as the latent... 

Bromomethyl-3,4-dibromo-3,4-dihydrocoumarin 1 (Fig. 11.4) and its chloro-methylated analogue 2b rapidly and progressively inactivate a-chymotrypsin and also the activities of a series of trypsin-like proteases. A benzyl substituent characteristic of good substrates of a-chymotrypsin was introduced at the 3-position to make inhibition more selective. This substituted dihydrocoumarin 3 irreversibly inhibited a-chymotrypsin and other proteases. These functionalized six-membered aromatic lactones, and their five- and seven-membered counterparts, 3//-benzofuran-2-ones 2a26 and 4,5-dihydro-3//-benzo[b]oxepin-2-ones 2c,27 were the first efficient suicide inhibitors of serine proteases. Their postulated mechanism of action is shown in Scheme 11.2. 

However, there are two problems with these unconjugated lactones lack of selectivity and limited stability of the inhibitor in biological buffers. Coumarin carboxylates have been developed to improve selectivity toward a given serine protease (Section 11.4.1). On the other hand, the amide bond is chemically and enzymatically much more stable than the ester one. This raised the question of whether a starting functionalized lactam behaved like the previous lactones and generated in situ a quinonimine methide, the aza-analogue of the quinone methide (Section 11.5). 

DPP-4 is a serine protease that inactivates GLP-1. GLP-1 stimulates insulin secretion and suppresses glucagon release. The inhibition of DPP-4 prolongs the half-life of GLP-1 and brings about beneficial effects on glucose levels and glucose tolerance in type 2 diabetics. Backes et al. [64] report on the parallel optimization of enzyme binding affinity and inhibition, selectivity, ADME properties, and PK (Scheme 19). 

Scallan, M.J., Raj, B.K.M., Calvo, B., Garin-Chesa, P., Sanz-Moncasi, M.P., Healey, J.H., Old, L.J. and Rettig, W.J. (1994) Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblast of epithelial cancers. Proceedings of the National Academy of Sciences ofthe United States of America, 91, 5657-5661. 

This approach was first applied toward an understanding of discriminating interactions in the serine proteases factor Xa, thrombin and trypsin [108] and provided selectivity information for all important serine protease subpockets, which are in agreement to experimental selectivities of typical protease inhibitors. This approach was complemented by a 3-D-QSAR selectivity analysis on a series of 3-amidinobenzyl-lH-indole-2-carboxamides [107], which points, from the viewpoint of the ligands, to similar main interactions driving selectivity between key enzymes in the blood... 

Whiting AK, Peticolas WL (1994) Biochemistry 33 552-561 Selected reference with emphasis on the LBHB character of serine proteases oxy anion hole... 

Interestingly, the selectivity of the hydoxamic acid inhibitor of DPP IV was crucial in experiments to establish the role and existence of quiescent cell proline dipeptidase, QPP, a serine protease whose inhibition leads to the death of quiescent peripheral blood monocytes [104]. All other DPP IV inhibitors did not exhibit sufficient selectivity to discriminate between DPP IV and QPP. 

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