LeBeau Aaron M, Singh Pratap, Isaacs John T, Denmeade Samuel R
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Chem Biol. 2008 Jul 21;15(7):665-74. doi: 10.1016/j.chembiol.2008.05.020.
Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a K(i) for PSA of 65 nM. The inhibitor had a 60-fold higher K(i) for chymotrypsin. A validated model of PSA's catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme.
前列腺癌细胞会产生高（微克至毫克/毫升）水平的丝氨酸蛋白酶前列腺特异性抗原（PSA）。PSA在前列腺癌周围的细胞外液中具有酶活性，但在循环系统中的浓度要低1000至10000倍，在循环系统中它因与大量血清蛋白酶抑制剂结合而失活。前列腺癌部位高水平活性PSA的独特存在，使得PSA成为靶向成像和治疗的一个有吸引力的候选物。一种基于肽底物的合成方法首先鉴定出了肽醛，然后是PSA的硼酸抑制剂。其中最佳的抑制剂序列为Cbz-Ser-Ser-Lys-Leu-(boro)Leu，对PSA的抑制常数（K(i)）为65 nM。该抑制剂对胰凝乳蛋白酶的K(i)值高60倍。一个经过验证的PSA催化位点模型证实了抑制剂与PSA酶内残基之间的关键相互作用。
