Protein tyrosine phosphatase 1B (PTP1B) is a validated target for developing antiobesity, antidiabetic and anticancer drugs. Over the past years, several inhibitors of PTP1B have been discovered; however, none has been approved by the drug regulatory agencies. Interestingly, the research programs focused on discovering PTP1B inhibitors typically use truncated structures of the protein (PTP1B_1-300, 1–300 amino acids), leading to the loss of valuable information about the inhibition and selectivity of ligands and repeatedly misleading the optimization of putative drug leads. Up to date, only six inhibitors of the full-length protein (hPTP1B_1-400), with affinity constants ranging from 1.3 × 10⁴ to 3.3 × 10⁶ M⁻¹, have been reported. Towards the discovery of new ligands of the full-length human PTP1B (hPTP1B_1-400) from natural sources, herein we describe the isolation of a γ-lactone (1, butyrolactone I) from the fungus Aspergillus terreus, as well as the semisynthesis, inhibitory properties (in vitro and in silico), and the structure-activity relationship of a set of butyrolactone derivatives (1 and 2, and 6–12) as hPTP1B_1-400 inhibitors, as well as the affinity constant (k_a = 2.2 × 10⁵ M⁻¹) of the 1-hPTP1B₁–₄₀₀ complex, which was determined by fluorescence quenching experiments, after the inner filter effect correction.

蛋白酪氨酸磷酸酶1B（PTP1B）是开发抗肥胖，抗糖尿病和抗癌药物的有效靶标。在过去的几年中，已经发现了几种PTP1B抑制剂。但是，尚未有任何药物监管机构批准。有趣的是，专注于发现PTP1B抑制剂的研究程序通常使用蛋白质的截短结构（PTP1B _{1-300，1–300}个氨基酸），导致丢失了有关配体抑制和选择性的有价值的信息，并一再误导了PTP1B抑制剂的优化。推定的药物线索。迄今为止，只有六种全长蛋白抑制剂（h PTP1B _1-400），亲和常数范围为1.3×10 ⁴至3.3×10 ⁶ M^-1，已被报道。为了从自然来源中发现全长人PTP1B（h PTP1B _1-400）的新配体，我们在此描述了从土曲霉（Aspergillus terreus）真菌中分离出γ-内酯（1，丁内酯I）的方法。半合成，抑制特性（体外和计算机模拟）以及一组作为h PTP1B _1-400抑制剂的丁内酯衍生物（1和2和6-12）的结构-活性关系以及亲和常数（k _a  = 2.2×10 ⁵1 - h PTP1B ₁ – _400配合物的M ^-1），在内部滤镜效果校正后，通过荧光猝灭实验确定。