The Spt-Ada-Gcn5 acetyltransferase (SAGA) transcriptional coactivator contains a four-protein subcomplex called the deubiquitinating enzyme (DUB) module that removes ubiquitin from histone H2B-K120. The human DUB module contains the catalytic subunit ubiquitin-specific protease 22 (USP22), which is overexpressed in a number of cancers that are resistant to available therapies. We screened a massive combinatorial library of cyclic peptides and identified potent inhibitors of USP22. The top hit was highly specific for USP22 compared with a panel of 44 other human DUBs. Cells treated with peptide had increased levels of H2B monoubiquitination, demonstrating the ability of the cyclic peptides to enter human cells and inhibit H2B deubiquitination. These macrocycle inhibitors are, to our knowledge, the first reported inhibitors of USP22/SAGA DUB module and show promise for development.

Spt-Ada-Gcn5 乙酰转移酶 (SAGA) 转录共激活因子包含一种称为去泛素化酶 (DUB) 模块的四蛋白亚复合体，可从组蛋白 H2B-K120 中去除泛素。人类 DUB 模块包含催化亚基泛素特异性蛋白酶 22 (USP22)，它在许多对可用疗法有抵抗力的癌症中过度表达。我们筛选了一个庞大的环肽组合文库，并确定了 USP22 的有效抑制剂。与一组 44 个其他人类 DUB 相比，最高命中对 USP22 具有高度特异性。用肽处理的细胞具有增加的 H2B 单泛素化水平，表明环肽能够进入人体细胞并抑制 H2B 去泛素化。据我们所知，这些大环抑制剂是