Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II

Swedberg, Joakim E.; Ghani, Hafiza Abdul; Harris, Jonathan M.; Veer, Simon J. de; Craik, David J.

doi:10.1021/acsmedchemlett.8b00422

Cited by 26 publications

(30 citation statements)

References 34 publications

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“…3). AEPs are typically produced as inactive proenzymes and require auto-activation at low pH (4)(5)(6); conditions that are typically encountered in plant vacuoles [23][24][25] . Therefore, we incubated recombinantly expressed pro-MCoAEP2 (~54 kDa) at pH 4 to produce the mature active enzyme (~32-35 kDa; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Together with their natural function as host defense agents 4 , cyclotides have shown promise as scaffolds for biotechnological applications. In particular, the Momordica cochinchinensis trypsin inhibitor-I/II (MCoTI-I and MCoTI-II) cyclotides are increasingly being exploited as pharmaceutical scaffolds [5][6][7] . However, the cyclization of synthetic peptides in vitro remains challenging 8 .…”

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confidence: 99%

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A bifunctional asparaginyl endopeptidase efficiently catalyzes both cleavage and cyclization of cyclic trypsin inhibitors

et al. 2020

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Asparaginyl endopeptidases (AEPs) catalyze the key backbone cyclization step during the biosynthesis of plant-derived cyclic peptides. Here, we report the identification of two AEPs from Momordica cochinchinensis and biochemically characterize MCoAEP2 that catalyzes the maturation of trypsin inhibitor cyclotides. Recombinantly produced MCoAEP2 catalyzes the backbone cyclization of a linear cyclotide precursor (MCoTI-II-NAL) with a k cat /K m of 620 mM −1 s −1 , making it one of the fastest cyclases reported to date. We show that MCoAEP2 can mediate both the N-terminal excision and C-terminal cyclization of cyclotide precursors in vitro. The rate of cyclization/hydrolysis is primarily influenced by varying pH, which could potentially control the succession of AEP-mediated processing events in vivo. Furthermore, MCoAEP2 efficiently catalyzes the backbone cyclization of an engineered MCoTI-II analog with anti-angiogenic activity. MCoAEP2 provides enhanced synthetic access to structures previously inaccessible by direct chemistry approaches and enables the wider application of trypsin inhibitor cyclotides in biotechnology applications.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

A bifunctional asparaginyl endopeptidase efficiently catalyzes both cleavage and cyclization of cyclic trypsin inhibitors

et al. 2020

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“…Nevertheless, the demonstration that WW domains are potentially druggable (30) and the high specificity of viral L domain interactions with their cognate protein domains support further investigations into this approach to control egress of RNA viruses like EBOV. In support of strategic shifts in drug discovery efforts, recent successes have been achieved with the use of stapled peptides (166 -168) and cell-penetrating cyclic peptides (68), which are designed to target specific intracellular protein-protein interactions. Indeed, Zhang et al (168) demonstrated that stapled peptides targeting dimer formation of the HIV-1 capsid protein showed potent antiviral activity against a broad array of viral isolates, including strains that were resistant to reverse transcriptase and protease inhibitors.…”

Section: Filoviruses and Other Ppxy-containing Virusesmentioning

confidence: 99%

Viruses go modular

Shepley-McTaggart

Fan

Sudol

et al. 2020

Journal of Biological Chemistry

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The WW domain is a modular protein structure that recognizes the proline-rich Pro-Pro-x-Tyr (PPxY) motif contained in specific target proteins. The compact modular nature of the WW domain makes it ideal for mediating interactions between proteins in complex networks and signaling pathways of the cell (e.g. the Hippo pathway). As a result, WW domains play key roles in a plethora of both normal and disease processes. Intriguingly, RNA and DNA viruses have evolved strategies to hijack cellular WW domain-containing proteins and thereby exploit the modular functions of these host proteins for various steps of the virus life cycle, including entry, replication, and egress. In this review, we summarize key findings in this rapidly expanding field, in which new virus-host interactions continue to be identified. Further unraveling of the molecular aspects of these crucial virus-host interactions will continue to enhance our fundamental understanding of the biology and pathogenesis of these viruses. We anticipate that additional insights into these interactions will help support strategies to develop a new class of small-molecule inhibitors of viral PPxY-host WW-domain interactions that could be used as antiviral therapeutics. . 2 The abbreviations used are: PPxY, proline-proline-x-tyrosine motif; AdV, adenovirus; ART protein, arrestin-related trafficking protein; BAG3, BCL2associated athanogene 3; BUL1 and -2, binds ubiquitin ligase proteins 1 and 2; CASA, chaperone-assisted selective autophagy; CIRF, cell-intrinsic restriction factor; EBV, Epstein-Barr virus; EBOV, Ebola virus; ESCRT, endosomal sorting complex required for transport; HECT, homologous to the E6AP carboxyl terminus (E3 ligase family); HHV, human herpes virus; HTLV-1, human T-cell leukemia virus 1; IFITM3, interferon-induced transmembrane protein 3; ISG15, interferon stimulated gene 15; ITCH (AIP4), Itchy E3 ubiquitin protein ligase; LDI-1 and -2, late domain-interacting proteins 1 and 2; L domain, viral late domain; LMP2A, latent membrane protein 2A; MARV, Marburg virus; MLV, murine leukemia virus; Nedd4, neuronal precursor cell-expressed developmentally down-regulated 4; PVI, preprotein VI (membrane lytic internal capsid protein); Rsp5, yeast reverses SPTphenotype protein 5 (E3 ubiquitin-protein ligase); RSV, Rous sarcoma virus; SMURF1 and -2, Smad ubiquitin-regulating factors 1 and 2; TBSV, tomato bushy stunt virus; Tsg101, tumor susceptibility gene 101; VLP, virus-like particle; VSV, vesicular stomatitis virus; WOX1, WW domain-containing oxidoreductase; WWP1 and -2, WW domain-containing E3 ubiquitin protein ligase 1 and 2; MS, multiple sclerosis. cro REVIEWS 4604

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“…The trypsin inhibition activity of cf ‐MCoTI‐II‐L5 was subsequently determined and compared with that of chemically synthesized MCoTI‐II (Figure S13). The K i values of 0.0041 and 0.0050 n m , respectively, were comparable with the previously reported K i value of native MCoTI‐II (0.0023 n m ) . In general, the identification of this second ligation site in loop 5 of MCoTI‐II ( L5 : …CRGN // GY…) represents a viable alternative to the one described in loop 1 ( L1 : …VCPK // IL…) and opens up the possibility of a modular synthesis of MCoTI‐II.…”

Section: Figurementioning

confidence: 99%

Efficient Enzymatic Cyclization of Disulfide‐Rich Peptides by Using Peptide Ligases

et al. 2019

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Disulfide-rich macrocyclic peptides-cyclotides, for examplerepresent ap romisingc lass of molecules with potential therapeutic use. Despite their potential their efficient synthesis at large scale still represents am ajor challenge. Here we report new chemoenzymatic strategies using peptide ligase variants-inter alia, omniligase-1-fort he efficient and scalable one-pot cyclization and folding of the native cyclotides MCoTI-II, kalata B1 and variants thereof, as well as of the q-defensin RTD-1. The synthesis of the kB1 variant T20K was successfully demonstrated at multi-gram scale. The existence of several ligations ites for each macrocycle makes this approach highly flexible and facilitates both the larger-scale manufacture and the engineering of bioactive, grafted cyclotide variants, therefore clearly offering av aluable and powerful extension of the existing toolbox of enzymes for peptide head-to-tail cyclization.In the last decade macrocyclic peptides have gained increased traction as ap romising class of therapeutics. High metabolic stabilityt han their linear analogues, often accompanied by higher potency,m aket hem excellent leads in drug design.

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Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II

Cited by 26 publications

References 34 publications

A bifunctional asparaginyl endopeptidase efficiently catalyzes both cleavage and cyclization of cyclic trypsin inhibitors

A bifunctional asparaginyl endopeptidase efficiently catalyzes both cleavage and cyclization of cyclic trypsin inhibitors

Viruses go modular

Efficient Enzymatic Cyclization of Disulfide‐Rich Peptides by Using Peptide Ligases

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