Mendes Flávia Carneiro, de Paiva Janine Cerqueira, da Silva Elói Quintas Gonçalves, Santos Marcus Rebouças, de Almeida Lima Graziela Domingues, Moreira Gabriela Alves, Silva Lucas Viana Gomes, de Melo Agripino Joice, de Souza Ana Paula Martins, de Oliveira Mendes Tiago Antônio, Machado-Neves Mariana, Teixeira Róbson Ricardo, Silva-Júnior Abelardo, Fietto Juliana Lopes Rangel, de Oliveira Leandro Licursi, Bressan Gustavo Costa
Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil.
Universidade Federal de Viçosa, Departamento de Veterinária, Viçosa, MG, Brazil.
Life Sci. 2022 Oct 15;307:120849. doi: 10.1016/j.lfs.2022.120849. Epub 2022 Aug 1.
The serine/arginine-rich protein kinases (SRPK) specifically phosphorylate their substrates at RS-rich dipeptides, which are abundantly found in SR splicing factors. SRPK are classically known for their ability to affect the splicing and expression of gene isoforms commonly implicated in cancer and diseases associated with infectious processes. Non-splicing functions have also been attributed to SRPK, which highlight their functional plasticity and relevance as therapeutic targets for pharmacological intervention. In this sense, different SRPK inhibitors have been developed, such as the well-known SRPIN340 and its derivatives, with anticancer and antiviral activities. Here we evaluated the potential immunomodulatory activity of SRPIN340 and three trifluoromethyl arylamide derivatives. In in vitro analysis with RAW 264.7 macrophages and primary splenocytes, all the compounds modulated the expression of immune response mediators and antigen-presentation molecules related to a tendency for M2 macrophage polarization. Immunization experiments were carried out in mice to evaluate their potential as vaccine immunostimulants. When administrated alone, the compounds altered the expression of immune factors at the injection site and did not produce macroscopic or microscopic local reactions. In addition, when prepared as an adjuvant with inactivated EHV-1 antigens, all the compounds increased the anti-EHV-1 neutralizing antibody titers, a change that is consistent with an increased Th2 response. These findings demonstrate that SRPIN340 and its derivatives exhibit a noticeable capacity to modulate innate and adaptative immune cells, disclosing their potential to be used as vaccine adjuvants or in immunotherapies.
富含丝氨酸/精氨酸的蛋白激酶（SRPK）特异性地在富含RS二肽处磷酸化其底物，这些二肽在SR剪接因子中大量存在。SRPK传统上以其影响基因异构体的剪接和表达的能力而闻名，这些异构体通常与癌症以及与感染过程相关的疾病有关。非剪接功能也归因于SRPK，这突出了它们作为药理学干预治疗靶点的功能可塑性和相关性。从这个意义上说，已经开发了不同的SRPK抑制剂，例如著名的SRPIN340及其衍生物，它们具有抗癌和抗病毒活性。在这里，我们评估了SRPIN340和三种三氟甲基芳基酰胺衍生物的潜在免疫调节活性。在用RAW 264.7巨噬细胞和原代脾细胞进行的体外分析中，所有化合物都调节了与M2巨噬细胞极化趋势相关的免疫反应介质和抗原呈递分子的表达。在小鼠中进行免疫实验以评估它们作为疫苗免疫刺激剂的潜力。当单独给药时，这些化合物改变了注射部位免疫因子的表达，并且没有产生宏观或微观的局部反应。此外，当与灭活的EHV-1抗原作为佐剂制备时，所有化合物都增加了抗EHV-1中和抗体滴度，这一变化与Th2反应增加一致。这些发现表明，SRPIN340及其衍生物表现出显著的调节先天性和适应性免疫细胞的能力，揭示了它们用作疫苗佐剂或用于免疫治疗的潜力。
