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Molecules 2017, 22(11), 1829; doi:10.3390/molecules22111829

Inhibition of Human Kallikrein 5 Protease by Triterpenoids from Natural Sources

1
Tsumura Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
2
Department of Dermatology, Tohoku University Graduate School of Medicine, Miyagi 980-8574, Japan
*
Author to whom correspondence should be addressed.
Received: 29 September 2017 / Revised: 16 October 2017 / Accepted: 24 October 2017 / Published: 27 October 2017
(This article belongs to the Special Issue Biological Activity of Secondary Metabolites)
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Abstract

Stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is involved in the cell renewal and maintenance of the skin barrier function. The excessive activation of KLK5 causes an exacerbation of dermatoses, such as rosacea and atopic dermatitis. Some triterpenoids are reported to suppress the serine proteases. We aimed to investigate whether bioactive triterpenoids modulate the KLK5 protease. Nineteen triterpenoids occurring in medicinal crude drugs were evaluated using an enzymatic assay to measure the anti-KLK5 activity. The KLK5-dependent cathelicidin peptide LL-37 production in human keratinocytes was examined using immunoprecipitation and Western blotting. Screening assays for evaluating the anti-KLK5 activity revealed that ursolic acid, oleanolic acid, saikosaponin b1, tumulosic acid and pachymic acid suppressed the KLK5 protease activity, although critical molecular moieties contributing to anti-KLK5 activity were unclarified. Ursolic acid and tumulosic acid suppressed the proteolytic processing of LL-37 in keratinocytes at ≤10 μM; no cytotoxicity was observed. Both triterpenoids were detected in the plasma of rats administered orally with triterpenoid-rich crude drug Jumihaidokuto. Our study reveals that triterpenoids, such as ursolic acid and tumulosic acid, modulate the KLK5 protease activity and cathelicidin peptide production. Triterpenoids may affect the skin barrier function via the regulation of proteases. View Full-Text
Keywords: kallikrein 5; kallikrein 7; triterpenoid; ursolic acid; tumulosic acid; Jumihaidokuto; skin barrier; cathelicidin; LL-37 kallikrein 5; kallikrein 7; triterpenoid; ursolic acid; tumulosic acid; Jumihaidokuto; skin barrier; cathelicidin; LL-37
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Matsubara, Y.; Matsumoto, T.; Koseki, J.; Kaneko, A.; Aiba, S.; Yamasaki, K. Inhibition of Human Kallikrein 5 Protease by Triterpenoids from Natural Sources. Molecules 2017, 22, 1829.

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