Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4‑boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

治疗癌症、心血管疾病和其他疾病需要γ-谷氨酰转肽酶（GGT1，又名γ-谷氨酰转移酶）抑制剂。抑制 GGT1 的化合物已在临床中进行了评估，但尚无抑制剂成功证明具有特异性和全身性的 GGT1 抑制作用。所有这些都有严重的副作用。L-2-氨基-4-硼丁酸 ( l -ABBA) 是一种谷氨酸类似物，是体外最有效的 GGT1 抑制剂。在这项研究中，我们解析了活性位点结合有 ABBA 的人 GGT1 (hGGT1) 的晶体结构。研究该结构以确定酶和抑制剂之间的相互作用。基于这些数据，设计并合成了一系列新型 ABBA 类似物。测定了它们对 hGGT1 水解和转肽活性的抑制活性。先导化合物用 hGGT1 结晶并解析结构。复合物的动力学数据和结构为蛋白质结构动力学在开发抑制 hGGT1 的化合物中的关键作用提供了新的见解。