Swedberg Joakim E, Ghani Hafiza Abdul, Harris Jonathan M, de Veer Simon J, Craik David J
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia.
ACS Med Chem Lett. 2018 Nov 21;9(12):1258-1262. doi: 10.1021/acsmedchemlett.8b00422. eCollection 2018 Dec 13.
Kallikrein-related peptidase 4 (KLK4) is a serine protease that has putative intracellular and extracellular functions in prostate cancer progression. Here we show that MCoTI-II, a 34-amino acid cyclic peptide found in the seeds of red gac (), is an inhibitor of KLK4. By grafting a preferred KLK4 cleavage sequence into MCoTI-II, we produced a highly potent KLK4 inhibitor ( = 0.1 nM) that displayed 100,000-fold selectivity over related KLKs and the ability to penetrate cells. Additionally, by substituting positively charged noncontact residues in this compound, we produced a potent and selective KLK4 inhibitor that does not penetrate cells. The inhibitors were shown to be nontoxic to human cells and stable in human serum. These KLK4 inhibitors provide useful chemical tools to further define the role(s) of both intracellular and extracellular KLK4 in prostate cancer cell lines and disease models.
激肽释放酶相关肽酶4（KLK4）是一种丝氨酸蛋白酶，在前列腺癌进展中具有假定的细胞内和细胞外功能。在此我们表明，红瓜种子中发现的一种34个氨基酸的环肽MCoTI-II是KLK4的抑制剂。通过将优选的KLK4切割序列嫁接到MCoTI-II中，我们制备了一种高效的KLK4抑制剂（ = 0.1 nM），其对相关激肽释放酶的选择性超过100,000倍，并且具有穿透细胞的能力。此外，通过替换该化合物中带正电荷的非接触残基，我们制备了一种有效的、选择性的KLK4抑制剂，该抑制剂不会穿透细胞。这些抑制剂对人细胞无毒，并且在人血清中稳定。这些KLK4抑制剂为进一步确定细胞内和细胞外KLK4在前列腺癌细胞系和疾病模型中的作用提供了有用的化学工具。
