Structure-guided design of CPPC-paired disulfide-rich peptide libraries for ligand and drug discovery.
Structure-guided design of CPPC-paired disulfide-rich peptide libraries for ligand and drug discovery.
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DOI：
10.1039/d2sc00924b
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发表时间：
2022-07-06
期刊：
影响因子：
8.4
通讯作者：
Wu, Chuanliu
中科院分区：
文献类型：
--
作者：
Wu, Yapei;Fan, Shihui;Dong, Meng;Li, Jinjing;Kong, Chuilian;Zhuang, Jie;Meng, Xiaoting;Lu, Shuaimin;Zhao, Yibing;Wu, Chuanliu
通过多个二硫键限制的肽（或富含二硫键的肽，DRP）已经成为配体和药物发现的新兴前沿。这种肽具有将生物制剂的结合能力与小分子的稳定性和生物利用度联合收割机结合的潜力。然而，具有稳定的三维（3D）结构的DRP通常是天然来源的或从天然的工程。在这里，我们报告了具有稳定的3D结构（即，CPPC-DRPs）。从随机或结构收敛肽库中设计或选择了一系列新的CPPC-DRP。因此，我们首次揭示了CPPC-DRP可以通过利用独特的二聚体CPPC小环的约束来保持多样化的3D结构，包括不规则结构和规则的α-螺旋和β-折叠。使用我们的DRP发现平台，还成功发现并鉴定了可以特异性结合细胞表面受体（CD 28）的新CPPC-DRP。总的来说，这项研究提供了一个非常规的肽结构空间的基础，以前无法通过天然DRP和计算设计，启发新的肽配体和治疗的发展。通过合理的文库设计和筛选，发现了具有稳定3D结构的CPPC配对的富含二硫键的肽，为开发新的肽治疗剂提供了非常规的肽支架。
Peptides constrained through multiple disulfides (or disulfide-rich peptides, DRPs) have been an emerging frontier for ligand and drug discovery. Such peptides have the potential to combine the binding capability of biologics with the stability and bioavailability of smaller molecules. However, DRPs with stable three-dimensional (3D) structures are usually of natural origin or engineered from natural ones. Here, we report the discovery and identification of CPPC (cysteine–proline–proline–cysteine) motif-directed DRPs with stable 3D structures (i.e., CPPC–DRPs). A range of new CPPC–DRPs were designed or selected from either random or structure–convergent peptide libraries. Thus, for the first time we revealed that the CPPC–DRPs can maintain diverse 3D structures by taking advantage of constraints from unique dimeric CPPC mini-loops, including irregular structures and regular α-helix and β-sheet folds. New CPPC–DRPs that can specifically bind the receptors (CD28) on the cell surface were also successfully discovered and identified using our DRP-discovery platform. Overall, this study provides the basis for accessing an unconventional peptide structure space previously inaccessible by natural DRPs and computational designs, inspiring the development of new peptide ligands and therapeutics. CPPC-paired disulfide-rich peptides with stable 3D structures have been discovered through rational library design and screening, providing unconventional peptide scaffolds for the development of new peptide therapeutics.
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影响因子：
64.8
作者：
Chevalier A;Silva DA;Rocklin GJ;Hicks DR;Vergara R;Murapa P;Bernard SM;Zhang L;Lam KH;Yao G;Bahl CD;Miyashita SI;Goreshnik I;Fuller JT;Koday MT;Jenkins CM;Colvin T;Carter L;Bohn A;Bryan CM;Fernández-Velasco DA;Stewart L;Dong M;Huang X;Jin R;Wilson IA;Fuller DH;Baker D
通讯作者：
Baker D
影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
影响因子：
6.6
作者：
Gunasekera, Sunithi;Daly, Norelle L.;Craik, David J.
通讯作者：
Craik, David J.
影响因子：
16.6
作者：
Guo, Ye;Sun, De-Meng;Tian, Chang-Lin
通讯作者：
Tian, Chang-Lin
影响因子：
16.6
作者：
Lui, Bonny Gaby;Salomon, Nadja;Sahin, Ugur
通讯作者：
Sahin, Ugur