Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
CONCEPT Lab, Istituto Italiano di Tecnologia (IIT), Via E. Melen, 83, I-16152, Genova, Italy.
Eur J Med Chem. 2022 Dec 5;243:114781. doi: 10.1016/j.ejmech.2022.114781. Epub 2022 Sep 19.
Suppressors of cytokine signaling 1 (SOCS1) protein, a negative regulator of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that mimetics of KIR-SOCS1 can be potent therapeutics in several disorders (e.g., neurological, autoimmune or cardiovascular diseases). In this work, starting from a recently identified cyclic peptidomimetic of KIR-SOCS1, icPS5(Nal1), to optimize the peptide structure and improve its biological activity, we designed novel derivatives, containing crucial amino acids substitutions and/or modifications affecting the ring size. By combining microscale thermophoresis (MST), Circular Dichroism (CD), Nuclear Magnetic Resonance (NMR) and computational studies, we showed that the cycle size plays a key role in the interaction with JAK2 and the substitution of native residues with un-natural building blocks is a valid tool to maintain low-micromolar affinity toward JAK2, greatly increasing their serum stability. These findings contribute to increase the structural knowledge required for the recognition of SOCS1/JAK2 and to progress towards their conversion into more drug-like compounds.
细胞因子信号转导抑制因子 1（SOCS1）蛋白是 Janus 激酶（JAK）-信号转导子和转录激活子（STAT）途径的负调节剂，它具有一个小的激酶抑制区（KIR），参与 JAK 激酶的抑制。多项研究表明，KIR-SOCS1 的类似物在多种疾病（如神经、自身免疫或心血管疾病）中具有强大的治疗作用。在这项工作中，我们从最近鉴定的 KIR-SOCS1 的环状肽模拟物 icPS5（Nal1）开始，优化肽结构并提高其生物活性，设计了新型衍生物，包含关键氨基酸取代和/或修饰，影响环大小。通过结合微量热泳动（MST）、圆二色性（CD）、核磁共振（NMR）和计算研究，我们表明环大小在与 JAK2 的相互作用中起着关键作用，用非天然构建块取代天然残基是维持对 JAK2 的低微摩尔亲和力的有效工具，极大地提高了它们的血清稳定性。这些发现有助于增加对 SOCS1/JAK2 识别所需的结构知识，并朝着将其转化为更具类药性的化合物的方向前进。
