Plant cystine‐knot peptides: pharmacological perspectives

Abstract

Cystine-knot miniproteins are a class of 30-50 amino acid long peptides widespread in eukaryotic organisms. Due to their very peculiar three-dimensional structure, they exhibit high resistance to heat and peptidase attack. The cystine-knot peptides are well represented in several plant species including medicinal herbs and crops. The pharmacological interest in plant cystine-knot peptides derives from their broad biological activities, mainly cytotoxic, antimicrobial and peptidase inhibitory and in the possibility to engineer them to incorporate pharmacophoric information for oral delivery or disease biomonitoring. The mechanisms of action of plant cystine-knot peptides are still largely unknown, although the capacity to interfere with plasma membranes seems a feature common to several cystine-knot peptides. In some cases, such as potato carboxypetidase inhibitor (PCI) and tomato cystine-knot miniproteins (TCMPs), the cystine-knot peptides target human growth factor receptors either by acting as growth factor antagonist or by altering their signal transduction pathway. The possibility to identify specific molecular targets of plant cystine-knot peptides in human cells opens novel possibilities for the pharmacological use of these peptides besides their use as scaffold to develop stable disease molecular markers and therapeutic agents.

Efficacy of Plant Antimicrobials as Preservative in Food

“…Plant knottins contain 30 amino acids and comprises inhibitors of α-amylase, trypsin and carboxypeptidase families as well as cyclotides. They perform several functions like enzyme-inhibitory, cytotoxic, antimicrobial, insecticidal and anti-HIV activities [72,73]. Initially, it was identified as protease inhibitors [74].…”

Bioinspired Designs, Molecular Premise and Tools for Evaluating the Ecological Importance of Antimicrobial Peptides

“…Contrary to the α-helical peptides, those that adopt the β-sheet conformations contain at least two Cys residues that form between 1 and 5 intramolecular disulfide bonds [ 60 ] that stabilize the tertiary structure of the peptides and confer substantial resistance to heat, protease and enzymatic inactivation [ 61 , 62 ]. β-hairpin structures are also common for those containing 2–4 Cys residues e.g., protegrin-1 [ 63 ].…”

The Tomato Metallocarboxypeptidase Inhibitor I, which Interacts with a Heavy Metal-Associated Isoprenylated Protein, Is Implicated in Plant Response to Cadmium

“…PIs are crucial components for cellular homeostasis and survival, and participate in several physiological processes, such as the mobilization of storage proteins in seeds, the regulation of endogenous enzymatic activities, and the protection against pests [2,3]. In addition to proteins with higher molecular mass such as serpins, the PI group comprises small/medium range polypeptides (<15 kDa), which include inhibitors of metallocarboxypeptidase and cyclotides [1,4]. Small polypeptide-based PIs are generally composed by a single domain including specific secondary structural elements and disulfide bridges.…”

“…The C-terminal glycine (Gly39) of the PCI is cleaved-off by the protease exposing Val38, whose carboxylate group coordinates with Zn 2+ in the protease active site, blocking catalytic activity [7,9].Plant cystine-knot metallocarboxypeptidase inhibitors possess bioactivity also in mammalian cells, since they can target human growth factor receptors either acting as an antagonist of growth factor for receptor binding or by altering their signal transduction pathways [5,[10][11][12]. Due to their bioactivity and highly-stable structural scaffold, cystine-knot proteins have received great attention for pharmacological application to develop diagnostic markers and therapeutic agents (for a review see [4]). Regarding the role of cystine-knot proteins in plants, it was demonstrated that PCIs accumulate in potato tubers and in leaves after wounding [13,14] and after treatment with abscisic acid (ABA) and jasmonate [14].…”

“…Plant cystine-knot metallocarboxypeptidase inhibitors possess bioactivity also in mammalian cells, since they can target human growth factor receptors either acting as an antagonist of growth factor for receptor binding or by altering their signal transduction pathways [5,[10][11][12]. Due to their bioactivity and highly-stable structural scaffold, cystine-knot proteins have received great attention for pharmacological application to develop diagnostic markers and therapeutic agents (for a review see [4]).…”