Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications.
Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications.
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DOI：
10.1002/cbic.201600253
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发表时间：
2016-09-02
期刊：
影响因子：
3.2
通讯作者：
Roberts, Richard W.
中科院分区：
文献类型：
--
作者：
Fiacco, Stephen V.;Kelderhouse, Lindsay E.;Hardy, Amanda;Peleg, Yonatan;Hu, Biliang;Ornelas, Argentina;Yang, Peiying;Gammon, Seth T.;Howell, Shannon M.;Wang, Pin;Takahashi, Terry T.;Millward, Steven W.;Roberts, Richard W.
Peptides typically have poor biostabilities and natural sequences cannot easily be converted into drug-like molecules without extensive medicinal chemistry. We have adapted mRNA display to evolve highly stable cyclic peptides while preserving target affinity. To do this, we incorporated an unnatural 21st amino acid in an mRNA display library which was subjected to proteolysis prior to selection for function. The resulting “SUPR peptide” (Scanning Unnatural Protease Resistant) showed ∼500-fold improvement in serum stability (t1/2 = 160 hours) and up to 3,700-fold improvement in protease resistance versus the parent sequence. We extended this approach by carrying out SUPR peptide selections against Her2-positive cells in culture. The resulting SUPR4 peptide showed low nanomolar affinity toward Her2, excellent specificity, and selective tumor uptake in vivo. These results argue that this is a general method to design potent and stable peptides for in vivo imaging and therapy. Two-stage directed evolution of mRNA Display libraries containing unnatural N-methyl amino acids results in highly stable cyclic peptides with antibody-like affinities and specificities. This technique was employed to select a nanomolar affinity unnatural cyclic peptide for the Her2 receptor which showed rapid tumor uptake and minimal non-specific background in mouse models of Her2-positive breast cancer.
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