Oxidative degradation of sequence-defined peptoid oligomers
Oxidative degradation of sequence-defined peptoid oligomers
复制标题
序列定义的类肽寡聚体的氧化降解
DOI：
10.1039/d2me00179a
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发表时间：
2023
影响因子：
3.6
通讯作者：
Rosales, Adrianne M.
中科院分区：
文献类型：
--
作者：
Schunk, Hattie C.;Austin, Mariah J.;Taha, Bradley Z.;McClellan, Matthew S.;Suggs, Laura J.;Rosales, Adrianne M.
由于其N-取代，类肽通常被认为是抵抗生物降解的，如酶和水解性机制。这种稳定性对于治疗开发来说是一个特别有吸引力的特征，也是许多先前生物学研究的卖点。然而，另一种关键的降解模式仍有待充分探索，即由活性氧和氮物种(ROS/RNS)介导的氧化降解。ROS和RNS在生物材料可能存在的许多情况下具有生物学意义。因此，提高对类肽氧化敏感性的理解对于充分挖掘其在生物材料领域的潜力至关重要，在生物材料领域，一个氧化不稳定但酶稳定的分子可以提供有吸引力的特性。为此，我们展示了在化学生成的ROS存在的情况下序列定义的类肽链的基本特征，与ROS敏感的肽(如脯氨酸和赖氨酸低聚体)相比。赖氨酸低聚物对ROS和胰酶的降解速度最快。类肽在金属催化氧化条件下的降解速率与多(脯氨酸)相当，同时保持了对酶降解的抵抗力。此外，含有赖氨酸的多肽-类肽杂化分子在ROS介导和酶介导的降解中都表现出可调性，其降解速率介于赖氨酸和类肽低聚体之间。当类似赖氨酸的侧链被结合到类肽骨架中时，降解速度与赖氨酸肽低聚物相匹配，但仍对酶降解具有抵抗力。这些结果将对类肽降解的理解扩展到氧化和酶机制，并展示了类肽结合到材料中的潜力，这些材料需要选择性地进行氧化降解，或者需要定向的酶敏感性。
Due to their N-substitution, peptoids are generally regarded as resistant to biological degradation, such as enzymatic and hydrolytic mechanisms. This stability is an especially attractive feature for therapeutic development and is a selling point of many previous biological studies. However, another key mode of degradation remains to be fully explored, namely oxidative degradation mediated by reactive oxygen and nitrogen species (ROS/RNS). ROS and RNS are biologically relevant in numerous contexts where biomaterials may be present. Thus, improving understanding of peptoid oxidative susceptibility is crucial to exploit their full potential in the biomaterials field, where an oxidatively-labile but enzymatically stable molecule can offer attractive properties. Toward this end, we demonstrate a fundamental characterization of sequence-defined peptoid chains in the presence of chemically generated ROS, as compared to ROS-susceptible peptides such as proline and lysine oligomers. Lysine oligomers showed the fastest degradation rates to ROS and the enzyme trypsin. Peptoids degraded in metal catalyzed oxidation conditions at rates on par with poly(prolines), while maintaining resistance to enzymatic degradation. Furthermore, lysine-containing peptide–peptoid hybrid molecules showed tunability in both ROS-mediated and enzyme-mediated degradation, with rates intermediate to lysine and peptoid oligomers. When lysine-mimetic side-chains were incorporated into a peptoid backbone, the rate of degradation matched that of the lysine peptide oligomers, but remained resistant to enzymatic degradation. These results expand understanding of peptoid degradation to oxidative and enzymatic mechanisms, and demonstrate the potential for peptoid incorporation into materials where selectivity towards oxidative degradation is necessary, or directed enzymatic susceptibility is desired.