Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer
Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer
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DOI：
10.1016/j.bmc.2009.06.012
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发表时间：
2009-07-15
影响因子：
3.5
通讯作者：
Denmeade, Samuel R.
中科院分区：
文献类型：
--
作者：
LeBeau, Aaron M.;Banerjee, Sangeeta R.;Denmeade, Samuel R.
前列腺特异性抗原（PSA）是一种丝氨酸蛋白酶生物标志物，可能在前列腺癌的发展和进展中发挥作用。用小分子抑制剂抑制PSA的酶活性是一个有吸引力的，但尚未开发的目标。以前，我们报道了一系列基于肽醛和硼酸的PSA抑制剂。在这项研究中，在P2和P3位置的肽为基础的PSA抑制剂的结构要求进行了探索，通过在这些位置的一系列天然和非天然氨基酸的取代。该分析证明了P2位置中的疏水残基和P3位置中具有氢键潜力的氨基酸的偏好。使用该信息，鉴定了具有序列Cbz-Ser-Ser-Gln-Nle-（boro）-Leu的肽硼酸抑制剂，PSA的Ki为25 nM。将大体积金属螯合基团连接到该肽的氨基末端不会对PSA抑制产生不利影响。这一结果表明，PSA抑制剂螯合物的平台可以被开发为用于前列腺癌的SPECT或基于PET的成像剂。(C)2009爱思唯尔有限公司保留所有权利。
Prostate-specific antigen (PSA) is a serine protease biomarker that may play a role in prostate cancer development and progression. The inhibition of PSA's enzymatic activity with small molecule inhibitors is an attractive and, as of yet, unexploited target. Previously, we reported a series of peptidyl aldehyde and boronic acid based inhibitors of PSA. In this study, the structural requirements in the P2 and P3 positions of peptide-based PSA inhibitors are explored through the substitution of a series of natural and unnatural amino acids in these positions. This analysis demonstrated a preference for hydrophobic residues in the P2 position and amino acids with the potential to hydrogen bond in the P3 position. Using this information, a peptide boronic acid inhibitor with the sequence Cbz-Ser-Ser-Gln-Nle-(boro)-Leu was identified with a K-i for PSA of 25 nM. The attachment of a bulky metal chelating group to the amino terminal of this peptide did not adversely affect PSA inhibition. This result suggests that a platform of PSA inhibitor chelates could be developed as SPECT or PET-based imaging agents for prostate cancer. (C) 2009 Elsevier Ltd. All rights reserved.