Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry.
Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry.
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DOI：
10.1172/jci91512
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发表时间：
2018-04-02
期刊：
影响因子：
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通讯作者：
Sewell AK
中科院分区：
文献类型：
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作者：
Miles JJ;Tan MP;Dolton G;Edwards ES;Galloway SA;Laugel B;Clement M;Makinde J;Ladell K;Matthews KK;Watkins TS;Tungatt K;Wong Y;Lee HS;Clark RJ;Pentier JM;Attaf M;Lissina A;Ager A;Gallimore A;Rizkallah PJ;Gras S;Rossjohn J;Burrows SR;Cole DK;Price DA;Sewell AK
多肽疫苗可以有效激活人类T细胞，但生物稳定性较差，这限制了运输物流和体内治疗活性。合成生物学有潜力通过使用自然界中不存在的亚基生成高度稳定的抗原“模拟物”来解决这些限制。我们开发了一个基于 D-氨基酸组合化学的平台，并使用该平台对完全人工的 CD8+ T 细胞激动剂进行逆向工程，该激动剂反映了流感病毒天然表位蓝图的免疫原性特征。这种非天然肽在人血清和胃酸中高度稳定，反映了对物理和酶降解的内在抵抗力。在体外，合成激动剂刺激并扩展了多功能人流感病毒特异性 CD8+ T 细胞的原型库。在体内，通过皮下接种疫苗在首次接触的人源化小鼠中引发了特异性反应，从而提供了针对随后的致命流感攻击的保护。此外，合成激动剂口服后具有免疫原性。这项概念验证研究强调了合成生物学在扩大疫苗设计和治疗递送视野方面的力量。
Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic “mimics” using subunits that do not exist in the natural world. We developed a platform based on D–amino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus. This nonnatural peptide was highly stable in human serum and gastric acid, reflecting an intrinsic resistance to physical and enzymatic degradation. In vitro, the synthetic agonist stimulated and expanded an archetypal repertoire of polyfunctional human influenza virus–specific CD8+ T cells. In vivo, specific responses were elicited in naive humanized mice by subcutaneous vaccination, conferring protection from subsequent lethal influenza challenge. Moreover, the synthetic agonist was immunogenic after oral administration. This proof-of-concept study highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery.