Identification and characterization of highly versatile peptide-vectors that bind non-competitively to the low-density lipoprotein receptor for in vivo targeting and delivery of small molecules and protein cargos.
Identification and characterization of highly versatile peptide-vectors that bind non-competitively to the low-density lipoprotein receptor for in vivo targeting and delivery of small molecules and protein cargos.
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DOI：
10.1371/journal.pone.0191052
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Khrestchatisky M
中科院分区：
文献类型：
--
作者：
David M;Lécorché P;Masse M;Faucon A;Abouzid K;Gaudin N;Varini K;Gassiot F;Ferracci G;Jacquot G;Vlieghe P;Khrestchatisky M
药物的膜渗透不足，特别是生物治疗药物和/或低靶标特异性仍然是其疗效的主要缺点。我们在此提出合理的表征和优化多肽作为载体开发的靶细胞表达特定受体参与胞吞或胞吞。参与受体介导转运的受体包括LDL受体。筛选在细胞系中稳定表达的人LDLR （hLDLR）上的复杂噬菌体显示肽库，鉴定出特异性结合hLDLR的环状和线性肽家族。VH411铅环肽允许有效载荷（如S-Tag肽或抗体）内吞进入表达hLDLR的细胞。该导联肽载体的体积减小和化学优化导致受体亲和力的提高。优化后的肽载体成功地偶联到不同性质和大小的载体上，包括小有机分子、sirna、肽或蛋白质片段（如Fc片段）。我们表明，在所有情况下，肽载体保持其与hLDLR的结合亲和力和内吞作用的潜力。在野生型或ldlr-/-小鼠中静脉注射后，c端化学偶联或融合到肽载体上的Fc片段在ldlr富集的器官中显示出显著的生物分布。因此，我们开发了高度通用的多肽载体，具有对LDLR作为靶受体的良好亲和力。这些肽载体具有进一步发展的潜力，可以有效地将治疗或显像剂运送到表达LDLR的细胞（包括病理细胞）或器官中。
Insufficient membrane penetration of drugs, in particular biotherapeutics and/or low target specificity remain a major drawback in their efficacy. We propose here the rational characterization and optimization of peptides to be developed as vectors that target cells expressing specific receptors involved in endocytosis or transcytosis. Among receptors involved in receptor-mediated transport is the LDL receptor. Screening complex phage-displayed peptide libraries on the human LDLR (hLDLR) stably expressed in cell lines led to the characterization of a family of cyclic and linear peptides that specifically bind the hLDLR. The VH411 lead cyclic peptide allowed endocytosis of payloads such as the S-Tag peptide or antibodies into cells expressing the hLDLR. Size reduction and chemical optimization of this lead peptide-vector led to improved receptor affinity. The optimized peptide-vectors were successfully conjugated to cargos of different nature and size including small organic molecules, siRNAs, peptides or a protein moiety such as an Fc fragment. We show that in all cases, the peptide-vectors retain their binding affinity to the hLDLR and potential for endocytosis. Following i.v. administration in wild type or ldlr-/- mice, an Fc fragment chemically conjugated or fused in C-terminal to peptide-vectors showed significant biodistribution in LDLR-enriched organs. We have thus developed highly versatile peptide-vectors endowed with good affinity for the LDLR as a target receptor. These peptide-vectors have the potential to be further developed for efficient transport of therapeutic or imaging agents into cells -including pathological cells—or organs that express the LDLR.
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影响因子：
3.8
作者：
Kawamoto M;Horibe T;Kohno M;Kawakami K
通讯作者：
Kawakami K
影响因子：
15.9
作者：
FONG, LG;BONNEY, E;COOPER, AD
通讯作者：
COOPER, AD
DOI：
10.1161/atvbaha.108.179564
发表时间：
2009-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Goldstein JL;Brown MS
通讯作者：
Brown MS
影响因子：
28.5
作者：
Firer MA;Gellerman G
通讯作者：
Gellerman G
影响因子：
56.9
作者：
Cwirla, SE;Balasubramanian, P;Dower, WJ
通讯作者：
Dower, WJ