School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
J Med Chem. 2023 Jul 13;66(13):8628-8642. doi: 10.1021/acs.jmedchem.3c00283. Epub 2023 Jun 18.
Nonsubstrate allosteric inhibitors of P-glycoprotein (Pgp), which are considered promising modulators for overcoming multidrug resistance (MDR), are relatively unknown. Herein, we designed and synthesized amino acids bearing amide derivatives of pyxinol, the main ginsenoside metabolite produced by the human liver, and examined their MDR reversal abilities. A potential nonsubstrate inhibitor () was identified to undergo high-affinity binding to the putative allosteric site of Pgp at the nucleotide-binding domains. Subsequent assays confirmed that (25 μM) was able to suppress both basal and verapamil-stimulated Pgp-ATPase activities (inhibition rates of 87 and 60%, respectively) and could not be pumped out by Pgp, indicating that it was a rare nonsubstrate allosteric inhibitor. Moreover, interfered with Pgp-mediated Rhodamine123 efflux while exhibiting high selectivity for Pgp. Notably, also markedly enhanced the therapeutic efficacy of paclitaxel, with a tumor inhibition ratio of 58.1%, when used to treat nude mice bearing KBV xenograft tumors.
非底物变构抑制剂 P-糖蛋白（Pgp），被认为是克服多药耐药（MDR）的有前途的调节剂，目前还知之甚少。本文设计并合成了用人肝产生的主要人参皂苷代谢物吡嗪醇的酰胺衍生物作为氨基酸，并考察了它们的 MDR 逆转能力。鉴定出一种潜在的非底物抑制剂 () 与 Pgp 在核苷酸结合域的假定变构位点具有高亲和力结合。随后的测定证实， （25 μM）能够抑制基础和维拉帕米刺激的 Pgp-ATP 酶活性（分别抑制率为 87%和 60%），并且不能被 Pgp 泵出，表明它是一种罕见的非底物变构抑制剂。此外， 干扰 Pgp 介导的 Rhodamine123 外排，同时对 Pgp 具有高选择性。值得注意的是， 还显著提高了紫杉醇的治疗效果，当用于治疗携带 KBV 异种移植肿瘤的裸鼠时，肿瘤抑制率为 58.1%。
