Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting.
Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting.
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优化了用于肿瘤靶向的 αvβ6 整合素结合肽的血清稳定性和特异性。
DOI：
10.1016/j.jbc.2021.100657
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Sellers DL
中科院分区：
文献类型：
--
作者：
Cardle II;Jensen MC;Pun SH;Sellers DL
整合素αvβ6是一种在健康组织中表达水平较低，但在肿瘤发生过程中表达水平上调的抗原，这使其成为癌症成像和治疗的一个有希望的靶点。A20FMDV2是一种源自口蹄疫病毒的20聚肽，与其他整合素相比，对αvβ6表现出纳米级和选择性亲和力。尽管具有这种选择性，但由于A20FMDV2的血清稳定性较差，其在体内成像和治疗αvβ6+肿瘤方面的成功有限。在此，我们探索了A20FMDV2肽的环化和修饰，以提高其血清稳定性，同时不牺牲其对αv - β6的亲和力和特异性。利用半胱氨酸取代和十氟联苯全氟环化，我们合成了6个环化的A20FMDV2变体，发现其中2个保留了与αvβ6的结合，血清稳定性略有提高。进一步的d-氨基酸替换和环化区外的c端序列优化大大延长了肽的血清稳定性，而不降低结合亲和力。与原始肽相比，环化的A20FMDV2变体显示出非特异性整合素结合增加，但发现与非天然氨基酸瓜氨酸、羟脯氨酸和d-丙氨酸的额外修饰可以恢复结合特异性，其中一些修饰导致αvβ6整合素的选择性比原始A20FMDV2肽更高。本文详细介绍的肽修饰极大地提高了利用A20FMDV2在体内靶向αvβ6的潜力，扩大了癌症靶向和治疗的机会。
The integrin αvβ6 is an antigen expressed at low levels in healthy tissue but upregulated during tumorigenesis, which makes it a promising target for cancer imaging and therapy. A20FMDV2 is a 20-mer peptide derived from the foot-and-mouth disease virus that exhibits nanomolar and selective affinity for αvβ6 versus other integrins. Despite this selectivity, A20FMDV2 has had limited success in imaging and treating αvβ6+ tumors in vivo because of its poor serum stability. Here, we explore the cyclization and modification of the A20FMDV2 peptide to improve its serum stability without sacrificing its affinity and specificity for αvβ6. Using cysteine amino acid substitutions and cyclization by perfluoroarylation with decafluorobiphenyl, we synthesized six cyclized A20FMDV2 variants and discovered that two retained binding to αvβ6 with modestly improved serum stability. Further d-amino acid substitutions and C-terminal sequence optimization outside the cyclized region greatly prolonged peptide serum stability without reducing binding affinity. While the cyclized A20FMDV2 variants exhibited increased nonspecific integrin binding compared with the original peptide, additional modifications with the non-natural amino acids citrulline, hydroxyproline, and d-alanine were found to restore binding specificity, with some modifications leading to greater αvβ6 integrin selectivity than the original A20FMDV2 peptide. The peptide modifications detailed herein greatly improve the potential of utilizing A20FMDV2 to target αvβ6 in vivo, expanding opportunities for cancer targeting and therapy.
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影响因子：
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作者：
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发表时间：
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期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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通讯作者：
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DOI：
10.1158/1078-0432.ccr-18-2665
发表时间：
2019-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hausner SH;Bold RJ;Cheuy LY;Chew HK;Daly ME;Davis RA;Foster CC;Kim EJ;Sutcliffe JL
通讯作者：
Sutcliffe JL