Plant Kunitz Inhibitors and Their Interaction with Proteases: Current and Potential Pharmacological Targets

Abstract

The action of proteases can be controlled by several mechanisms, including regulation through gene expression; post-translational modifications, such as glycosylation; zymogen activation; targeting specific compartments, such as lysosomes and mitochondria; and blocking proteolysis using endogenous inhibitors. Protease inhibitors are important molecules to be explored for the control of proteolytic processes in organisms because of their ability to act on several proteases. In this context, plants synthesize numerous proteins that contribute to protection against attacks by microorganisms (fungi and bacteria) and/or invertebrates (insects and nematodes) through the inhibition of proteases in these organisms. These proteins are widely distributed in the plant kingdom, and are present in higher concentrations in legume seeds (compared to other organs and other botanical families), motivating studies on their inhibitory effects in various organisms, including humans. In most cases, the biological roles of these proteins have been assigned based mostly on their in vitro action, as is the case with enzyme inhibitors. This review highlights the structural evolution, function, and wide variety of effects of plant Kunitz protease inhibitors, and their potential for pharmaceutical application based on their interactions with different proteases.

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

“…Previous studies have reported that C. dioscoridis extract exhibits antioxidant, antiinflammatory, anti-nociceptive, anti-hyperglycemic, and anti-diabetic activity [15][16][17][18][19]. Interestingly, several studies demonstrated the anticancer activity of the bioactive components and the crude extract of C.dioscoridis [20][21][22][23][24][25]. Several protease inhibitors from C.dioscoridis have been purified and characterized.…”

“…These protease inhibitors showed cytotoxic activity equal to the crude extract. They have been identified as potential antitumor targets because of their involvement in proteostasis [24,25]. Recently, El-Gamal et al (2021) confirmed that C.dioscoridis extract has anticancer and anti-aging activities as it showed significant inhibitory activity against hyaluronidase collagenase, tyrosinase and elastase [22].…”

Pleiotropic effects of recombinant protease inhibitors in plants

“…Genetic manipulation of plants also remains highly inefficient, without a routinely successful, genotype independent transformation protocol, and further insights onto the hurdles facing direct or indirect recombinant DNA technology, as well as its genetic, molecular, and regulatory element requirements are thoroughly discussed in a review by Basso et al (2020). For purposes of efficiently establishing new beneficial and widely functional protease inhibitors such as recombinant serine protease inhibitors (rBbKI), serine and cysteine inhibitors (rBbCI) derived from native inhibitors discovered from Bauhinia bauhinioides seeds, as well as serine and metalloprotease inhibitors from Enterolobium contortisiliquum seeds, more knowledge of their structure, selectivity and specificity to the different peptidase enzymes, including their target enzyme activity, must be gathered (Ferreira et al, 2019;Bonturi et al, 2022).…”

“…Additionally, protease inhibitors also exhibit direct interfering effects on endogenous proteases altering the physiological or compositional characteristics of the transgenic host plant. In this case, RPIs could rapidly interfere with the regulation of several metabolic processes such as the elimination of misfolded proteins, polypeptide pre-and pros-region processing during protein maturation and turnover of certain essential proteins (Solomon et al, 1999;Buono et al, 2019;Bonturi et al, 2022).…”

“…Furthermore, serine-type inhibitors bovine aprotinin and tomato Kunitz-type cathepsin D inhibitor expressed in potato caused altered leaf protein contents expressed ectopically in transgenic crop plants (Munger et al, 2012). Several latest studies still describe the use of recombinant protease inhibitors as potent pesticides (Shams and Bano, 2017;Bonturi et al, 2022); however, these herbivorous insects also developed various strategies to cope with the dietary protease inhibitors. These evolutionary strategies render the use of recombinant protease inhibitors ineffective as evolving pests also demonstrate the ability to overexpress proteolytic enzymes to outcompete inhibitory proteins, and likewise use alternative classes of proteases to improve their insensitivity against the inhibitors.…”