Ma Bohan, Liu Donghua, Zheng Mengjun, Wang Zhe, Zhang Dize, Jian Yanlin, Ma Jian, Fan Yizeng, Chen Yule, Gao Yang, Liu Jing, Li Xiang, Li Lei
Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710049, China.
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
JACS Au. 2024 Jan 29;4(2):816-827. doi: 10.1021/jacsau.3c00795. eCollection 2024 Feb 26.
Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder their widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, and limited membrane permeability. Nonetheless, while peptide stapling has successfully stabilized α-helical peptides, it has shown limited applicability for most β-sheet peptide motifs. In this study, we present the design of a novel double-stapled peptide capable of simultaneously stabilizing both α-helix and β-sheet structures. Our designed double-stapled peptide, named DSARTC, specifically targets the androgen receptor (AR) DNA binding domain and MDM2 as E3 ligase. Serving as a peptide-based PROTAC (proteolysis-targeting chimera), DSARTC exhibits the ability to degrade both the full-length AR and AR-V7. Molecular dynamics simulations and circular dichroism analysis validate the successful constraint of both secondary structures, demonstrating that DSARTC is a "first-in-class" heterogeneous-conformational double-stapled peptide drug candidate. Compared to its linear counterpart, DSARTC displays enhanced stability and an improved cell penetration ability. In an enzalutamide-resistant prostate cancer animal model, DSARTC effectively inhibits tumor growth and reduces the levels of both AR and AR-V7 proteins. These results highlight the potential of DSARTC as a more potent and specific peptide PROTAC for AR-V7. Furthermore, our findings provide a promising strategy for expanding the design of staple peptide-based PROTAC drugs, targeting a wide range of "undruggable" transcription factors.
肽类药物在治疗方面具有显著优势；然而，其稳定性有限和膜穿透能力不足阻碍了它们的广泛应用。克服这些挑战的一种策略是烃肽环化技术，该技术解决了诸如构象稳定性差、抗蛋白水解能力弱和膜通透性有限等问题。尽管如此，虽然肽环化已成功稳定了α-螺旋肽，但它对大多数β-折叠肽基序的适用性有限。在本研究中，我们展示了一种新型双环化肽的设计，该肽能够同时稳定α-螺旋和β-折叠结构。我们设计的双环化肽名为DSARTC，它特异性靶向雄激素受体（AR）DNA结合结构域和作为E3连接酶的MDM2。作为一种基于肽的PROTAC（蛋白酶靶向嵌合体），DSARTC具有降解全长AR和AR-V7的能力。分子动力学模拟和圆二色性分析验证了两种二级结构均成功受限，表明DSARTC是一种“同类首创”的异质构象双环化肽药物候选物。与其线性对应物相比，DSARTC表现出更高的稳定性和更好的细胞穿透能力。在恩杂鲁胺耐药的前列腺癌动物模型中，DSARTC有效抑制肿瘤生长并降低AR和AR-V7蛋白的水平。这些结果突出了DSARTC作为一种针对AR-V7更有效且特异的肽类PROTAC的潜力。此外，我们的研究结果为扩展基于环化肽的PROTAC药物设计提供了一种有前景的策略，可靶向多种“不可成药”的转录因子。
