Chemoenzymatic Synthesis of DNP-Functionalized FGFR1-Binding Peptides as Novel Peptidomimetic Immunotherapeutics for Treating Lung Cancer,Journal of Medicinal Chemistry

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Chemoenzymatic Synthesis of DNP-Functionalized FGFR1-Binding Peptides as Novel Peptidomimetic Immunotherapeutics for Treating Lung Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-15 , DOI: 10.1021/acs.jmedchem.4c00967
Xiaohui Li ₁ , Haiyan Liu ₂ , Shengjie Ding ₁ , Ziyu Tian ₁ , Jia Song ₁ , Huayu Zhong ₁ , Luwei Fu ₁ , Xiaojun Cai ₁ , Fengyu Huang ₁ , Kun Wang ₁ , Lilong Dong ₃ , Weixin Zhao ₃ , Yuepiao Cai ₁ , Shijie Dai ₁

Affiliation

Receptor-binding peptides are promising candidates for tumor target therapy. However, the inability to occupy “hot spots” on the PPI interface and rapid metabolic instability are significant limitations to their clinical application. We investigated a new strategy in which an FGFR1-binding peptide (Pep1) was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus. The resulting Pep1-DNP conjugates retained FGFR1 binding affinity and exhibited a similar potency in inhibiting FGF2-dependent cell proliferation, comparable to that of native Pep1 in vitro. In addition, three conjugates could recruit anti-DNP antibodies onto the surface of cancer cells, thereby mediating the CDC efficacy. In vivo pharmacokinetic studies and antitumor studies demonstrated that optimal conjugate 9 exhibited significantly prolonged half-lives and improved antitumor efficacy without prominent toxicity compared to those of native Pep1. This is a general and cost-effective approach for generating peptidomimetic immunotherapeutics with multiple antitumor mechanisms that may have broad applications in cancer therapy.

中文翻译：

化学酶法合成 DNP 功能化 FGFR1 结合肽作为治疗肺癌的新型拟肽免疫疗法

受体结合肽是肿瘤靶向治疗的有希望的候选者。然而，无法占据PPI界面上的“热点”和快速的代谢不稳定是其临床应用的重大限制。我们研究了一种新策略，其中 FGFR1 结合肽 (Pep1) 在 C 末端用二硝基苯基 (DNP) 半抗原进行位点特异性功能化。所得的 Pep1-DNP 缀合物保留了 FGFR1 结合亲和力，并在抑制 FGF2 依赖性细胞增殖方面表现出类似的效力，与体外天然 Pep1 相当。此外，三种缀合物可以将抗 DNP 抗体募集到癌细胞表面，从而介导 CDC 功效。体内药代动力学研究和抗肿瘤研究表明，与天然Pep1相比，最佳缀合物9表现出显着延长的半衰期和改善的抗肿瘤功效，且没有明显的毒性。这是一种通用且经济有效的方法，用于产生具有多种抗肿瘤机制的肽模拟免疫疗法，可能在癌症治疗中具有广泛的应用。

更新日期：2024-08-15

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