化疗引起的耐药性仍然是癌症复发和患者死亡的主要原因。 ATP 结合盒亚家族 B 成员 1 (ABCB1) 转运蛋白在肿瘤中过度表达会导致耐药性，但目前的 ABCB1 抑制剂在临床试验中尚未成功。为了应对这一挑战，我们提出了一种新策略，使用色氨酸作为开发 ABCB1 抑制剂的先导分子。我们的想法源于我们对蝙蝠细胞的研究，因为蝙蝠的癌症发病率较低，而 ABCB1 表达较高。我们假设蝙蝠中潜在的 ABCB1 底物可以作为人类的竞争性抑制剂。通过 ABCB1-底物相互作用的分子模拟，我们生成了一种苄基化环色氨酸 (C3N-Dbn-Trp2)，它可以抑制 ABCB1 活性，其功效与经典抑制剂维拉帕米相当或更好。 C3N-Dbn-Trp2 恢复了耐药人类癌细胞的化疗敏感性，且对细胞增殖没有不利影响。我们独特的方法为开发有效的 ABCB1 抑制剂来治疗耐药癌症提供了良好的前景。© 2024。作者。

Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers.© 2024. The Author(s).