Protease Inhibitors: Mechanisms

Abstract

Relatively few design principles underlie the mechanisms of inhibition of a myriad range of protease inhibitors. Protease inhibitors tend to be competitive and to compete with substrate binding, either through direct competition or deformation of the protease active site. Although protein inhibitors can gain potency through the burial of a large surface area and specificity through contacts with specific exosites, small‐molecule inhibitors primarily gain potency through interactions with the catalytic machinery of the enzyme and specificity through interactions with the substrate binding sites. Incorporation of these design principles into chemical probes and drugs have improved greatly our ability to create potent and specific protease inhibitors.

Mechanism of the Bis(imino)pyridine-Iron-Catalyzed Hydromagnesiation of Styrene Derivatives

“…6,39,[41][42][43][44][45][46][47][48][49] In contrast, nickel-catalyzed alkene hydromagnesiation has been proposed to proceed by direct β-hydride transfer from a nickel─alkyl species. 28 Thus, we wished to gain definitive insight into the mechanism of hydride transfer in iron-catalyzed hydromagnesiation. As the observation that the Grignard reagent had a significant influence on the regioselectivity contrasts proposals of a common iron hydride intermediate (vide supra), the isomerization of a β-aryl Grignard reagent was investigated (Scheme 4).…”

“…26 This type of hydride transfer has also been proposed for nickel-catalyzed hydromagnesiation. [27][28][29] However, it should be noted that these computations were based on an iron(II) cycle, which is unlikely under the highly reducing conditions of the reaction.…”

Abiotic Mimic of Endogenous Tissue Inhibitors of Metalloproteinases: Engineering Synthetic Polymer Nanoparticles for Use as a Broad-Spectrum Metalloproteinase Inhibitor

“…To realize efficacy, it is often necessary to incorporate multipoint interactions between the enzyme and the inhibitor. For example, small-molecule inhibitors often include combinations of interactions with both the catalytic group and the substrate-binding site (S-pocket), as binding to either individual element often will not provide sufficient selectivity/potency. − In addition to small-molecule inhibitors, multipoint interactions with peptides, proteins, and/or enzymes can also be realized with functional copolymers or nanoparticles (NPs). − Polymers/NPs may also inhibit target enzymes by binding in the vicinity of the active site, thereby blocking access to the active site ,,, or by an allosteric mechanism. , Conjugation of enzyme inhibitors/receptors to polymers/NPs represents another approach. ,, In one example the inhibitor benzamidine was incorporated in a trypsin-imprinted polymer particle to regulate its activity . Polymer inhibitors can offer an additional advantage over small-molecule inhibitors because of their molecular weight; binding to the enzyme can take place over a large surface area to enhance selectivity and/or potency .…”

Proteinaceous Protease Inhibitor fromLawsonia Inermis: Purification, Characterization and Antibacterial Activity

“…The protease inhibitor of L. inermis efficiently inhibited a broad range of proteases, which indicates that it would be probably inserted in the reactive loop of the active site of these proteases. Most protease inhibitors bind to proteases in a substrate-like manner and are hydrolyzed very slowly, but products are not formed [22]. The protease inhibitor of Moringa oleifera was also reported to inhibit a broad range of commercial and therapeutically important proteases [5].…”