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Review
. 2019 Sep;24(9):1877-1889.
doi: 10.1016/j.drudis.2019.05.026. Epub 2019 Jun 3.

Peptide-based Protease Inhibitors From Plants

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Free PMC article
Review

Peptide-based Protease Inhibitors From Plants

Roland Hellinger et al. Drug Discov Today. .
Free PMC article

Abstract

Proteases have an important role in homeostasis, and dysregulation of protease function can lead to pathogenesis. Therefore, proteases are promising drug targets in cancer, inflammation, and neurodegenerative disease research. Although there are well-established pharmaceuticals on the market, drug development for proteases is challenging. This is often caused by the limited selectivity of currently available lead compounds. Proteinaceous plant protease inhibitors are a diverse family of (poly)peptides that are important to maintain physiological homeostasis and to serve the innate defense machinery of the plant. In this review, we provide an overview of the diversity of plant peptide- and protein-based protease inhibitors (PIs), provide examples of such compounds that target human proteases, and discuss opportunities for these molecules in protease drug discovery and development.

Figures

Figure 1
Figure 1. Overview of the diversity and distribution of plant protease inhibitors (PIs).
(a) In total, 6720 inhibitors were identified; the percentage and number of inhibitors for the 12 main plant PI families are illustrated. Proteinaceous plant PIs account for almost half of PIs and peptide-like PIs result in a higher structural diversity. Overall, 81 plant families have been reported to express at least one PI. Importantly, four plant families account for ~66% of all known plant PIs to date: grasses (Poaceae 2139 PIs; 32% of all known PIs), legumes (Fabaceae 933 PIs, 14%), night shade (Solanaceae 732, 10%), and cabbage plants (Brassicaceae 632 PIs, 9%). The most important 22 plant families account for ~93.4% of all recorded plant PIs (these are in addition to those mentioned before: Violaceae 237 PIs, 3.5%; Saliaceae 218, 3.3%; Cucurbitaceae 192, 2.9%; Rosaceae 191, 2.9%; Malvaceae 138, 2.1%; Rubiaceae 120, 1.8%; Rutaceae 117, 1.7%; Asteraceae 116, 1.7%; Euphorbiaceae 93, 1.4%; Prymaceae 71, 1.1%; Amaranthaceae 50, 0.7 %; Moraceae 46, 0.7%; Lythraceae 45, 0.7%; Myrtaceae 44, 0.7%; Vitaceae 38, 0.6%; Musaceae 36, 0.5%; Nelumbonaceae 36, 0.5%; and Cannabaceae 35, 0.5%). The remaining 59 plant families contain ≤33 (~0.5%) inhibitors per plant, which in total accounts for approximately 6.6% of all recorded plant PIs. (b) For six plant families, an overview of the (normalized) distribution for the 12 inhibitor classes is shown. Many plant families are a rich source for multiple inhibitor types [e.g., Fabaceae and Solanaceae (seven different classes of PIs) or Poaceae and Cucurbitaceae (six different classes of PIs)]; other plant families exclusively express one to three plant PI types, for instance, violet plants (Violaceae), which are thought to contain only cyclotides, or the lopseed family (Phrymaceae), which contain phytostatins, serpin, and potato-type I inhibitors. Interestingly, Violaceae (cyclotides are the only inhibitors reported so far for this peptide class), Solanaceae (the prime source for potato type-II), and Cucurbitaceae (the major source for squash-TI) show a preference for a single to a few compound classes. (c) Plant PIs have been characterized for inhibition of prototypic proteases, including trypsin-, chymotrypsin-, elastase-, aspartic acid-like, and blood coagulation proteases. Representative inhibitors for each plant PI class were used to elucidate the previously tested inhibitory spectrum of the compound class, as indicated by connecting lines. Where applicable, inhibitory activity toward a nonhuman protease was converted to the human protease homolog in this illustration. In total, 200 human serine proteases comprise 19 families with numerous subfamilies, of which the S01 and S09 serine protease families are targeted by plant PIs; 28 families with a total of 169 cysteine proteases are known, of which plant PIs reportedly inhibit enzymes belonging to the C01 and C13 families. The metallocarboxypeptidase family M14 was reported as a protease target for plant PIs (56 families and 202 proteins). The A01 family of aspartic acid proteases is inhibited by plant PIs (three families, including 23 proteases). Human threonin proteases have not been reported as molecular targets for plant-derived PIs. Abbreviations: AAI/AATI, α-amylase and bifunctional trypsin inhibitors.
Figure 2
Figure 2. Representative structural models of plant protease inhibitors (PIs).
(a) At-serpin1 from Arabidopsis thaliana (PDB code: 3LE2) [63], (b) oryzacystatin-I from Oryza sativa (1EQK) [68], (c) Kunitz inhibitor from Cicer arietinum (5XOZ) [117], (d) soybean BBI from Glycine max (5J4Q) [118], (e) bifunctional α-amylase/trypsin inhibitor corn Hageman factor from Zea mays (1BEA) [89], (f) CMTI-V from Cucurbita maxima (1TIN) [93], (g) TI-II from Solanum lycopersicum (1PJU) [98], (h) potato CPI from Solanum tuberosum (1H20) [119], (i) mustard-TI from A. thaliana (1JXC) [120], (j) VcTI (2PLX) from Veronica hederifolia [107], (k) EETI-II from Ecballium elaterium (2IT7) [121], and (l) kalata B1 from Oldenlandia affinis (1NB1) [122]. Helices are shown in blue, β-sheets in red, disulfide bonds are indicated in yellow in stick representation, and connecting amino acid loops in gray. N- and C-termini are labeled, and the asterisk in (l) indicates the cyclization point of cyclotides. The inhibiting loops or other important sites for protease inhibition are marked with an arrow and explained further in the main text.

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