Peptides have recently garnered attention as middle-molecular-weight drugs with the characteristics of small molecules and macromolecules. Lysine-specific demethylase 1 (LSD1) is a potential therapeutic target for lung cancer, neuroblastoma, and leukemia, and some peptide-based LSD1 inhibitors designed based on the N-terminus of SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors, have been reported. The N-terminus of SNAIL1 peptide acts as a cap of the catalytic site of LSD1, inhibiting interactions with LSD1. However, the structure–activity relationship (SAR) of these inhibitors is not yet fully understood. Therefore, in the present study, we aimed to uncover the SAR and to identify novel SNAIL1 peptide-based LSD1 inhibitors. We synthesized peptide inhibitor candidates based on truncating the N-terminus of SNAIL1 or substituting its amino acid residues. In the truncation study, we found that SNAIL1 1–16 (2), which was composed of 16 residues, strongly inhibited LSD1. Furthermore, we investigated the SAR at residues-3 and -5 from the N-terminus and found that peptides 2j and 2k, in which leucine 5 of the parent peptide is substituted with unnatural amino acids, cyclohexylalanine and norleucine, respectively, strongly inhibited LSD1. This result suggests that the hydrophobic interaction between the inhibitor peptides and LSD1 affects the LSD1-inhibitory activity. We believe that this SAR information provides a basis for the development of more potent LSD1 inhibitors.

肽作为具有小分子和大分子特征的中等分子量药物，近年来受到人们的关注。赖氨酸特异性去甲基酶 1 (LSD1) 是肺癌、神经母细胞瘤和白血病的潜在治疗靶点，一些基于 SNAIL1（SNAIL/SCRATCH 转录因子家族成员）N 端设计的肽基 LSD1 抑制剂， 已经报道。 SNAIL1 肽的 N 末端充当 LSD1 催化位点的帽子，抑制与 LSD1 的相互作用。然而，这些抑制剂的构效关系（SAR）尚未完全了解。因此，在本研究中，我们的目的是揭示 SAR 并鉴定新型基于 SNAIL1 肽的 LSD1 抑制剂。我们通过截短 SNAIL1 的 N 末端或取代其氨基酸残基合成了候选肽抑制剂。在截短研究中，我们发现由16个残基组成的SNAIL1 1–16 ( 2 )强烈抑制LSD1。此外，我们研究了N端残基-3和-5的SAR，发现肽2j和2k（其中母肽的亮氨酸5分别被非天然氨基酸环己基丙氨酸和正亮氨酸取代）强烈抑制LSD1 。该结果表明抑制肽和LSD1之间的疏水相互作用影响LSD1抑制活性。我们相信，该 SAR 信息为开发更有效的 LSD1 抑制剂提供了基础。