Grassypeptolides as Natural Inhibitors of Dipeptidyl Peptidase 8 and T‐Cell Activation

Kwan, Jason C.; Liu, Yanxia; Ratnayake, Ranjala; Hatano, Ryo; Kuribara, Akiko; Morimoto, Chiko; Ohnuma, Kei; Paul, Valerie J.; Ye, Tao; Luesch, Hendrik

doi:10.1002/cbic.201300762

Cited by 21 publications

(24 citation statements)

References 34 publications

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“…Comparing IC 50 and K i values of 11 (IC 50 = 9 μM K i = 6.5 μM) and 7 (IC 50 = 100 μM K i = 83 μM), as it was expected, the inhibitory activity is attributable mainly to the aziridine site of miraziridine A. The IC 50 value of the synthetic miraziridine A (2 μM) was very similar to that reported for the natural product (2.1 μM).…”

Section: Miraziridine Asupporting

confidence: 80%

Natural Products as Cathepsin Inhibitors

Vidal‐Albalat

González

2016

Studies in Natural Products Chemistry

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Section: Miraziridine Asupporting

confidence: 80%

Natural Products as Cathepsin Inhibitors

Vidal‐Albalat

González

2016

Studies in Natural Products Chemistry

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“…148 This additional bioactivity indicates the potential of grassypeptolide as a probe to elucidate the functions of DPP8, a type of serine protease. 148 …”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 98%

“…19,52 The DPP8 inhibition by grassypeptolides 148 is rather unique among cyanobacterial compounds. Most of these serine protease inhibitors are cyclic depsipeptides bearing the modified glutamic acid residue, 3-amino-6-hydroxypiperidone (Ahp) (Fig 8).…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 99%

Biological targets and mechanisms of action of natural products from marine cyanobacteria

2015

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Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial.

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“…Many cyanobacterial metabolites are linear or cyclic modified peptides and depsipeptides with a propensity to inhibit various proteases with different potency and selectivity profiles. Examples of cyanobacterial compounds that have been found to inhibit proteases include: grassypeptolide A which inhibits the dipeptidyl peptidase 8 (DPP8), 1 gallinamide A (symplostatin 4) targeting cathepsin L, 2 and the potent elastase inhibitors lyngbyastatins 4–10. 3–6 A group of cyanobacterial protease inhibitors contain a characteristic statine (γ-amino-β-hydroxy acid) unit, which was first described in pepstatin A 7,8 and was found to confer activity towards aspartic proteases.…”

Section: Introductionmentioning

confidence: 99%

Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium

Al-Awadhi

Ratnayake

Paul

et al. 2016

Bioorganic & Medicinal Chemistry

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In search of novel protease inhibitors with therapeutic potential, our efforts exploring the marine cyanobacterium Lyngbya sp. have led to the discovery of tasiamide F (1), which is an analogue of tasiamide B (2). The structure was elucidated using a combination of NMR spectroscopy and mass spectrometry. The key structural feature in 1 is the presence of the Phe-derived statine core, which contributes to its aspartic protease inhibitory activity. The antiproteolytic activity of 1 and 2 was evaluated in vitro against cathepsins D and E, and BACE1. Tasiamide F (1) displayed IC50 values of 57 nM, 23 nM, and 0.69 μM, respectively, indicating greater selectivity for cathepsins over BACE1 compared with tasiamide B (2). Molecular docking experiments were carried out for compounds 1 and 2 against cathepsins D and E to rationalize their activity towards these proteases. The dysregulated activities of cathepsins D and E have been implicated in cancer and regulation of immune responses, respectively, and these proteases represent potential therapeutic targets.

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Grassypeptolides as Natural Inhibitors of Dipeptidyl Peptidase 8 and T‐Cell Activation

Cited by 21 publications

References 34 publications

Natural Products as Cathepsin Inhibitors

Natural Products as Cathepsin Inhibitors

Biological targets and mechanisms of action of natural products from marine cyanobacteria

Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium

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