Substrate mimetics

Celovsky, V. and Bordusa, F. (2000). Protease-catalyzed fragment condensation via substrate mimetic strategy a useful combination of solid-phase peptide synthesis with enzymatic methods. /. Pept. Res., 55, 325-9. 

Fig. 4. A selection of substrate mimetics evaluated as inhibitors of influenza virus sialidase.

Fig. 9. Substrate mimetics and chemoselectively N-glycosylation to the corresponding neoglyco-peptides as OT inhibitors.

Scheme 5.1.1. Schematic comparison of the binding of substrate mimetics and common acyl donors to the active site of proteases, on the basis of the ideas of the conventional binding model of proteases.

Besides linear peptides, the substrate mimetics approach also enables synthesis of isopeptides [11], The prerequisite for this activity is use of an iso-type of sub-... 

Scheme 5.1.2. Structures of substrates and substrate mimetic moieties for Arg- and Glu-specific proteases. 1. arginine 2. 4-amidinophenyl ester 3. 4-guanidinophenyl ester (OGp) 4. aspartic acid 5. glutamic acid 6. carboxymethyl thioester (SCm).

Scheme 5.1.3. Schematic representation of the synthesis of the all-D version of the WW domain of the human peptidyl-prolyl-c/s/tra/is-isomerase Pin 1 by use of substrate mimetics...

Scheme 5.1.4. General structures of linear 7 and iso-type 8 substrate mimetics. The site-specific ester leaving groups are emphasized by bold letters. PG, protecting group Ri, R2, individual side-chains R3, site-specific ester leaving group.

Animal proteases, particularly those involved in blood clotting, can be also regulated by endogenous protease inhibitory proteins that act as inhibitory substrate analogues. These inhibitor proteins bind at the active site through key inhibitory sequences in which the key residues about the peptide bond contribute to inhibition and are denoted (N-terminal side)—P2—PI—(peptide bond to be hydrolysed)-PT-P2 -(C-terminal side) or simply P2-P1-PT-P2. A large number of plant PI proteins also act as peptide substrate mimetics. 

The development of EPL has facilitated the production of large protein targets, but the requirement of specific N-terminal amino acids at the ligation site (cysteine [7], selenocysteine ]66J) reduces the general utilization of this method. Recently, we introduced a novel approach that we named expressed enzymatic ligation (EEL) for the semisynthesis of larger and chemically modified proteins that combines the advantages of the EPL with those of the substrate mimetic... 

Several 0-GlcNAcase inhibitors have been described, the most popular are streptozotocin (STZ) and PUGNAc. Both of these compounds are substrate mimetics that inhibit 0-GlcNAcase activity by resembling the natural substrate s ox-azoline transition state after its entrance into the active site (50, 51). Unfortunately, the above inhibitors are nonselective and can inhibit other glycosyl hydrolases therefore, they are a detriment to a multitude of cell pathways. Another, more potent transition state analog, A-acetylglucosamine-thiazoline (NAG-thiazoline), has been described recently (5). The increased potency likely is because the compound already resembles the oxazoline intermediate before it is exposed to the enzyme. Macauley et al. 

Scheme 10 Schematic Binding Model of Substrate Mimetics to Trypsinl ...

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