Grinberg Mihal, Zimering Mark B
Veterans Affairs New Jersey Healthcare System, East Orange, New Jersey, USA.
Endocrinol Diabetes Metab J. 2022 Dec;6(3). doi: 10.31038/EDMJ.2022631. Epub 2022 Dec 22.
The aim of the present study was to test whether conjugation of a synthetic peptide corresponding to a fragment of the second extracellular domain of the human serotonin 2A receptor substantially alters the in vivo pharmacodynamic blood pressure-lowering profile of the peptide in different hypertensive rat strains.
Sertuercept (SCLLADDN) was synthesized and modified using pegylation or myristolation. The two different peptide conjugates were tested in male Zucker diabetic fatty rats for acute and long-lasting blood pressure-lowering effects following single intraperitoneal administration. The myristolated Sertuercept was administered intraperitoneally to female Zucker fatty and male spontaneously hypertensive rats (SHR) and blood pressure was monitored either using tail cuff measurement (female Zucker) or by telemetry (SHR) rats. Plasma immunoglobulin G obtained by Protein G affinity chromatography in 25-week-old female Zucker or male spontaneously hypertensive rats was tested for binding to a linear synthetic peptide corresponding to the second extracellular loop of the serotonin 2A receptor. A cohort of male Zucker diabetic fatty rats was randomized to seven weeks of once-weekly myristolated Sertuercept or scrambled peptide (injections) and the kidneys were examined histologically for differences in total kidney lesions or fibrosis.
Pegylated Sertuercept promoted substantial blood pressure-lowering lasting approximately 30-48 hours in male Zucker diabetic fatty rats. Blood pressure-lowering following a single injection of Myristolated Sertuercept was much longer-lasting (6-11 days) and it was effective in male Zucker diabetic fatty rats, male spontaneously hypertensive rats and in a subset of hypertensive female Zucker fatty rats. Seven weeks' treatment with once-weekly Myristolated Sertuercept (2mg/kg) was associated with significantly fewer kidney lesions and less interstitial fibrosis compared to scrambled peptide in 25-week-old male Zucker diabetic fatty rats. Male spontaneously hypertensive rats (4 of 4 tested) harbored plasma IgG which bound significantly to serotonin 2A receptor peptide, and a subset of female Zucker fatty rats harboring IgG were responsive to blood pressure-lowering from the myristolated Sertuercept peptide.
Myristolated-Sertuercept, an epitope-specific peptide comprised of a portion of second extracellular loop of the human serotonin 2A receptor was safe, well-tolerated and effectively lowered blood pressure for one week or longer in two different strains of male hypertensive rats. These data provide proof-of-concept that once-weekly systemic drug administration is feasible to achieve not only long-lasting hypertension control, but also substantial renoprotection.
本研究旨在测试与人类5-羟色胺2A受体第二细胞外结构域片段相对应的合成肽的缀合是否会显著改变该肽在不同高血压大鼠品系中的体内药效学降压谱。
合成并使用聚乙二醇化或肉豆蔻酰化修饰Sertuercept（SCLLADDN）。在雄性Zucker糖尿病肥胖大鼠中单次腹腔注射后，测试这两种不同的肽缀合物的急性和长效降压作用。将肉豆蔻酰化的Sertuercept腹腔注射给雌性Zucker肥胖大鼠和雄性自发性高血压大鼠（SHR），并使用尾套测量法（雌性Zucker大鼠）或遥测法（SHR大鼠）监测血压。对通过蛋白G亲和层析从25周龄雌性Zucker大鼠或雄性自发性高血压大鼠获得的血浆免疫球蛋白G进行测试，以检测其与对应于5-羟色胺2A受体第二细胞外环的线性合成肽的结合情况。将一组雄性Zucker糖尿病肥胖大鼠随机分为两组，分别接受为期7周的每周一次肉豆蔻酰化Sertuercept或乱序肽（注射），并对肾脏进行组织学检查，以观察总肾损伤或纤维化的差异。
聚乙二醇化的Sertuercept在雄性Zucker糖尿病肥胖大鼠中促进了持续约30 - 48小时的显著降压。单次注射肉豆蔻酰化的Sertuercept后的降压作用持续时间长得多（6 - 11天），并且在雄性Zucker糖尿病肥胖大鼠、雄性自发性高血压大鼠以及一部分高血压雌性Zucker肥胖大鼠中有效。与25周龄雄性Zucker糖尿病肥胖大鼠中的乱序肽相比，每周一次肉豆蔻酰化的Sertuercept（2mg/kg）治疗7周与肾损伤显著减少和间质纤维化减轻相关。雄性自发性高血压大鼠（4只测试大鼠中的4只）体内的血浆IgG与5-羟色胺2A受体肽有显著结合，并且一部分携带IgG的雌性Zucker肥胖大鼠对肉豆蔻酰化的Sertuercept肽的降压作用有反应。
肉豆蔻酰化的Sertuercept是一种由人类5-羟色胺2A受体第二细胞外环的一部分组成的表位特异性肽，在两种不同品系的雄性高血压大鼠中安全、耐受性良好，并且能有效降低血压达一周或更长时间。这些数据提供了概念验证，即每周一次的全身给药不仅可行以实现持久的高血压控制，而且还能实现显著的肾脏保护。
