肽作为具有小分子和大分子特征的中等分子量药物最近受到关注。赖氨酸特异性脱甲基酶1(LSD1)是肺癌的潜在治疗靶点,神经母细胞瘤,和白血病,和一些基于肽的LSD1抑制剂,基于SNAIL1的N端设计,SNAIL/SCRATCH转录因子家族的成员,已被报道。SNAIL1肽的N端充当LSD1催化位点的帽,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,我们旨在揭示SAR并鉴定新型SNAIL1肽基LSD1抑制剂.我们基于截短SNAIL1的N-末端或取代其氨基酸残基合成了肽抑制剂候选物。在截断研究中,我们发现SNAIL11-16(2),由16个残基组成,强烈抑制LSD1。此外,我们研究了N末端残基-3和-5的SAR,发现肽2j和2k,其中亲本肽的亮氨酸5被非天然氨基酸取代,环己基丙氨酸和正亮氨酸,分别,强烈抑制LSD1。该结果表明抑制剂肽和LSD1之间的疏水相互作用影响LSD1抑制活性。我们相信这些SAR信息为开发更有效的LSD1抑制剂提供了基础。
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.