Samarasimhareddy Mamidi, Shamir Mai, Shalev Deborah E, Hurevich Mattan, Friedler Assaf
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Jerusalem, Israel.
Front Chem. 2020 May 19;8:405. doi: 10.3389/fchem.2020.00405. eCollection 2020.
Cyclic peptide-peptoid hybrids possess improved stability and selectivity over linear peptides and are thus better drug candidates. However, their synthesis is far from trivial and is usually difficult to automate. Here we describe a new rapid and efficient approach for the synthesis of click-based cyclic peptide-peptoid hybrids. Our methodology is based on a combination between easily synthesized building blocks, automated microwave assisted solid phase synthesis and bioorthogonal click cyclization. We proved the concept of this method using the INS peptide, which we have previously shown to activate the HIV-1 integrase enzyme. This strategy enabled the rapid synthesis and biophysical evaluation of a library of cyclic peptide-peptoid hybrids derived from HIV-1 integrase in high yield and purity. The new cyclic hybrids showed improved biological activity and were significantly more stable than the original linear INS peptide.
环肽 - 类肽杂合物比线性肽具有更高的稳定性和选择性，因此是更好的药物候选物。然而，它们的合成绝非易事，而且通常难以自动化。在此，我们描述了一种用于合成基于点击化学的环肽 - 类肽杂合物的快速高效新方法。我们的方法基于易于合成的构建模块、自动化微波辅助固相合成和生物正交点击环化的组合。我们使用INS肽证明了该方法的概念，我们之前已证明该肽可激活HIV - 1整合酶。该策略能够以高产率和高纯度快速合成并对源自HIV - 1整合酶的环肽 - 类肽杂合物文库进行生物物理评估。新的环杂合物显示出更好的生物活性，并且比原始的线性INS肽明显更稳定。
