美国华盛顿大学David Baker、Gaurav Bhardwaj等研究人员合作实现跨膜大环化合物的精确从头设计。相关论文于2022年8月29日在线发表在《细胞》杂志上。
研究人员利用计算设计加上实验表征，系统地研究了大环化合物膜渗透性和口服生物利用度的设计原则。研究人员设计了184个6-12个残基的大环化合物，其预测结构范围很广，含有非经典的主干修饰，实验确定的结构有35个；29个与计算模型非常接近。
通过这样的控制，研究人员表明，通过确保所有的酰胺（NH）基团参与内部氢键相互作用，可以系统地实现膜渗透性。在6-12个残基大小的范围内，有84种设计穿过膜，其渗透率大于1×10-6厘米/秒。具有暴露的NH基团的设计可以通过设计偏好脂膜的另一种等能全氢键状态来使其具有膜渗透性。稳健设计具有高结构精度的跨膜和口服生物利用性多肽的能力，会有助于下一代的大环治疗药物设计。
附：英文原文
Title: Accurate de novo design of membrane-traversing macrocycles
Author: Gaurav Bhardwaj, Jacob O’Connor, Stephen Rettie, Yen-Hua Huang, Theresa A. Ramelot, Vikram Khipple Mulligan, Gizem Gokce Alpkilic, Jonathan Palmer, Asim K. Bera, Matthew J. Bick, Maddalena Di Piazza, Xinting Li, Parisa Hosseinzadeh, Timothy W. Craven, Roberto Tejero, Anna Lauko, Ryan Choi, Calina Glynn, Linlin Dong, Robert Griffin, Wesley C. van Voorhis, Jose Rodriguez, Lance Stewart, Gaetano T. Montelione, David Craik, David Baker
Issue&Volume: 2022-08-29
Abstract: We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6–12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6–12 residue size range cross membranes with an apparent permeability greater than 1 × 106 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.
DOI: 10.1016/j.cell.2022.07.019
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00922-9