Stefan Katja, Namasivayam Vigneshwaran, Akhter Mst Tazmin, Gyimesi Gergely, Rafehi Muhammad, Busch Hauke, Trombik Tomasz, Luckenbach Till, König Jörg, Stefan Sven Marcel
University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck Institute of Experimental Dermatology, Medicinal Chemistry and Systems Polypharmacology, Ratzeburger Allee 160, 23538 Lübeck, Germany; University of Oslo and Oslo University Hospital, Department of Pathology, Rikshospitalet, Sognsvannsveien 20, 0372 Oslo, Norway.
University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck Institute of Experimental Dermatology, Medicinal Chemistry and Systems Polypharmacology, Ratzeburger Allee 160, 23538 Lübeck, Germany; University of Bonn, Pharmaceutical Institute, Department of Pharmaceutical and Cellbiological Chemistry, An der Immenburg 4, 53121 Bonn, Germany.
Biochem Pharmacol. 2025 Sep;239:117049. doi: 10.1016/j.bcp.2025.117049. Epub 2025 Jun 16.
Recently, we postulated the existence of 'multitarget binding sites', reoccurring structural motifs that interconnect otherwise structurally, functionally, and/or phylogenetically distant proteins. In this study, we functionally assessed a selection of 23 multitarget ATP-binding cassette (pan-ABC) transporter modulators against zebrafish (Danio rerio) organic anion transporting polypeptide (drOatp1d1), a transport protein of the solute carrier (SLC) superfamily. The zebrafish embryo is an important in vivo model in drug development to evaluate drug pharmacokinetics and pharmacodynamics. In total, 87.0 % of the compounds were identified as drOatp1d1 transport inhibitors, and the observed effects resembled the ones observed for human OATP1A2, OATP1B1, OATP1B3, and OATP2B1 despite the relative phylogenetic distance of drOatp1d1 to human OATPs. Potent hit molecules appeared to bind to a potential drOatp1d1 binding site derived from an OATP1B1 cryo-EM structure - strengthening the notion of common structural motifs between membrane transporters. The bioactivity of pranlukast (PRA) on human OATPs could be accurately predicted based on its activity on drOatp1d1. The collection of pan-ABC transporter modulators also showed activity against other zebrafish (i.e., drAbcb4) and non-zebrafish [i.e., murine Abca1 (mumAbca1)] membrane transporters, ultimately rendering it a suitable tool to translate between species to tackle the undruggability of membrane transporters and potentially other proteins by addressing conserved structural motifs.
最近，我们推测存在“多靶点结合位点”，即反复出现的结构基序，这些基序将原本在结构、功能和/或系统发育上相距甚远的蛋白质相互连接起来。在本研究中，我们对23种多靶点ATP结合盒（泛ABC）转运体调节剂进行了功能评估，它们作用于斑马鱼（Danio rerio）的有机阴离子转运多肽（drOatp1d1），这是溶质载体（SLC）超家族的一种转运蛋白。斑马鱼胚胎是药物开发中用于评估药物药代动力学和药效学的重要体内模型。总共87.0%的化合物被鉴定为drOatp1d1转运抑制剂，尽管drOatp1d1与人类OATP在系统发育上相对较远，但观察到的效应与人类OATP1A2、OATP1B1、OATP1B3和OATP2B1所观察到的效应相似。强效命中分子似乎与源自OATP1B1冷冻电镜结构的潜在drOatp1d1结合位点结合，这强化了膜转运体之间存在共同结构基序的观点。基于普仑司特（PRA）对drOatp1d1的活性，可以准确预测其对人类OATP的生物活性。泛ABC转运体调节剂的集合还显示出对其他斑马鱼（即drAbcb4）和非斑马鱼[即小鼠Abca1（mumAbca1）]膜转运体的活性，最终使其成为一个合适的工具，可用于跨物种转化，通过解决保守的结构基序来应对膜转运体以及潜在其他蛋白质难以成药的问题。
