從雞卵伴白蛋白水解物分離之前驅藥型胜肽以抑制血管收縮素轉化酶的作用   全文下載

One Peptide Derived from Hen Ovotransferrin as Pro-drug to Inhibit Angiotensin Converting Enzyme

從雞卵伴白蛋白的水解物所分離出一種對血管收縮素轉化?（angiotensin I-converting enzyme，aCe）具有抑制作用的胜?，並定出此一胜?之胺基酸序列為lys-Val-arg-Glu-Gly-thr-thr-tyr。此一胜?對aCe活性表現出濃度依存性的抑制效果；有效抑制濃度（IC50 value）為102.8 μM。若將lys-Val-arg-Glu-Gly-thr-thr-tyr與aCe反應後，所得到產物（lys-Val-arg-Glu-Gly-thr）的有效抑制濃度則變為9.1 μM；為反應前的11倍。因此，lys-Val-arg-Glu-Gly-thr-thr-tyr可視為前驅藥（pro-drug）。將lys-Val-arg-Glu-Gly-thr-thr-tyr與lys-Val-arg-Glu-Gly-thr再分別經由尾部靜脈注射至高血壓大白鼠（sHR）體內並觀察其血壓的變化。結果發現，lys-Val-arg-Glu-Gly-thr-thr-tyr於注射後40 min達到最高的降血壓值。可是，以相同的方法處理lys-Val-arg-Glu-Gly-thr，卻於靜脈注射後20 min就觀察到最高的降血壓值；此種出現降血壓時間的20 min差異可能是lys-Valarg-Glu-Gly-thr-thr-tyr於動物體內與aCe反應，轉化為活性型之抑制胜?（lys-Val-arg-Glu-Gly-thr）所需要的時間。因此，由以上結果可推論lys-Val-arg-Glu-Gly-thr-thr-tyr為一種前驅型（pro-drug）胜?，於動物體內被分解為lys-Val-arg-Glu-Gly-thr來抑制aCe的活性。

Angiotensin Ι-converting enzyme (ACE) inhibitory peptide was derived from hen ovotransferrin and identified as Lys-Val-Arg- Glu-Gly-Thr-Thr-Tyr. It produced a concentration-dependent inhibition of ACE activity in vitro with an IC50 value of 102.8 μM. After hydrolysis by ACE, the product (Lys-Val-Arg-Glu-Gly-Thr) has an IC50 value of 9.1 μM that was about 11-fold lower of the parent peptide. Thus, Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr can be considered as a pro-drug. Moreover, Lys-Val-Arg-Glu-Gly-Thr- Thr-Tyr and Lys-Val-Arg-Glu-Gly-Thr were intravenously administered into spontaneously hypertensive rats (SHR) to monitor the time-course change of systolic blood pressure. We found that Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr and its hydrolyzed product produced the maximal reduction of systolic blood pressure at 40 min and 20 min after injection, respectively. This 20 min delay might be considered as the time required for conversion of prodrug into Lys-Val-Arg-Glu-Gly-Thr, the true ACE inhibitor. In conclusion, the obtained results suggest that Lys-Val-Arg-Glu-Gly-Thr-Thr-Tyr works as the pro-drug of Lys-Val-Arg-Glu-Gly-Thr to inhibit ACE activity in vivo.