蜈蚣毒素多肽RhTx的高效化学合成及复性折叠研究

doi:10.6023/cjoc202102045

有机化学 ›› 2021, Vol. 41 ›› Issue (7): 2800-2809.DOI: 10.6023/cjoc202102045 上一篇下一篇

研究论文

蜈蚣毒素多肽RhTx的高效化学合成及复性折叠研究

王金艳^a, 董黎颖^a, 刘雅妮^a, 陈西同^a, 马艳楠^a, 尹昊^a, 杜姗姗^b^,^*(), 齐昀坤^a^,^*(), 王克威^a

a 青岛大学药学院山东青岛 266073
b 青岛科技大学化工学院山东青岛 266042

收稿日期:2021-02-24 修回日期:2021-03-24 发布日期:2021-04-12
通讯作者: 杜姗姗, 齐昀坤
作者简介:
† 共同第一作者(These authors contributed equally to this work).
基金资助:
国家自然科学基金(21807063); 国家自然科学基金(82003647); 国家自然科学基金(81870653); 中国博士后科学基金(2019M652307); 中国博士后科学基金(2020T130332); 山东省自然科学基金(ZR2019BH045); 山东省自然科学基金(ZR2020QH100)

Efficient Synthesis and Oxidative Folding Studies of Centipede Toxin RhTx

Jinyan Wang^a, Liying Dong^a, Ya'ni Liu^a, Xitong Chen^a, Yannan Ma^a, Hao Yin^a, Shanshan Du^b(), Yunkun Qi^a(), Kewei Wang^a

a School of Pharmacy, Qingdao University, Qingdao, Shandong 266073
b College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong 266042

Received:2021-02-24 Revised:2021-03-24 Published:2021-04-12
Contact: Shanshan Du, Yunkun Qi
Supported by:
National Natural Science Foundation of China(21807063); National Natural Science Foundation of China(82003647); National Natural Science Foundation of China(81870653); China Postdoctoral Science Foundation(2019M652307); China Postdoctoral Science Foundation(2020T130332); Natural Science Foundation of Shandong Province(ZR2019BH045); Natural Science Foundation of Shandong Province(ZR2020QH100)

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摘要/Abstract

二硫键的氧化折叠是合成二硫键构象锁定多肽的关键步骤. 前人发展的二硫键氧化折叠策略主要有一次氧化折叠、多次氧化折叠和一锅法氧化折叠. 目前对三种策略复性效率和收率等的比较性研究较少. 分别采用三种氧化折叠策略制备目标蜈蚣毒素多肽RhTx. 结果表明, 两次氧化折叠策略的分离收率高于一次和一锅法氧化折叠策略, 一锅法氧化折叠策略可能会导致较大比例的错误折叠. 探索了数十毫克量级RhTx的高效制备方法, 为进一步探索RhTx靶向TRPV1的结构机制等研究提供了工具分子. 此外, 对三种氧化折叠策略进行了系统比较, 为二硫键构象锁定多肽的合成提供了参考.

关键词: 二硫键, 二硫键构象锁定多肽, 氧化折叠, RhTx, 固相合成, 巯基保护基

The critical step for the synthesis of disulfide-containing peptides is the efficient construction of one or multiple disulfide bridges. Generally, the folding of disulfide bonds could be achieved by three chemical strategies,i.e. one-step oxidative folding strategy, multi-step oxidative folding strategy, and one-pot oxidative folding strategy. Because few comparative studies have been conducted on efficiencies of three strategies, the systematical research is desirable. Three folding strategies were separately applied for the preparation of centipede toxin RhTx. The results showed that the isolated yield of two-step oxidative folding strategy was higher than those of one-step and one-pot oxidative folding strategies. Besides, the one-pot oxidative folding strategy may induce severe misfoldings. The circular dichroism (CD) and activity tests indicated that disulfide bonds are critical for the structure and activity of RhTx. In addition, the efficient preparation of RhTx on tens of milligrams scale was achieved, affording molecular tools for the further biological and biophysical studies of RhTx targeting TRPV1. Overall, three mainstream oxidative folding strategies were systematically studied, which provided a valuable reference for the synthesis of disulfide-containing peptides.

Key words: disulfide bond, disulfide-containing peptide, oxidative folding, RhTx, solid phase peptide synthesis, thiol protecting group

引用此文

王金艳, 董黎颖, 刘雅妮, 陈西同, 马艳楠, 尹昊, 杜姗姗, 齐昀坤, 王克威. 蜈蚣毒素多肽RhTx的高效化学合成及复性折叠研究[J]. 有机化学, 2021, 41(7): 2800-2809.

Jinyan Wang, Liying Dong, Ya'ni Liu, Xitong Chen, Yannan Ma, Hao Yin, Shanshan Du, Yunkun Qi, Kewei Wang. Efficient Synthesis and Oxidative Folding Studies of Centipede Toxin RhTx[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2800-2809.

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图/表 6

图1. (A) RhTx的氨基酸序列、(B)线性肽1的合成及一次氧化折叠策略、(C)线性肽2的两次氧化折叠策略、(D)线性肽2的一锅法氧化折叠策略、(E)线性肽3的两次氧化折叠策略和(F)线性肽3的一锅法氧化折叠策略

Figure 1. (A) Amino acid sequences of RhTx, (B) synthetic route and one-step oxidative folding strategy of linear peptide 1, (C) two-step oxidative folding strategy of linear peptide 2, (D) one-pot oxidative folding strategy of linear peptide 2, (E) two-step oxidative folding strategy of linear peptide 3 and (F) one-pot oxidative folding strategy of linear peptide 3

图2. 肽1的一次氧化折叠RP-HPLC色谱图(λ=214 nm)

Figure 2. Analytical RP-HPLC chromatogram of one-step oxidative folding process of peptide 1 (λ=214 nm) (a)~(c) RP-HPLC spectra of folding solution for peptide 1. (d) RP-HPLC and ESI-MS spectra of purified peptide 4. The spectrum gave an observed mass of 2964.7 Da (calculated 2965.5 Da, average isotopes). RP-HPLC condition: a linear gradient of 10%~60% buffer B (0.08%~0.1% TFA in CH3CN) in buffer A (0.1% TFA in water) over 30 min (10% for 1 min, then 10%~60% for 30 min) on a Vydac C18 column

图3. (A)肽2和(B)肽3的两次氧化折叠RP-HPLC色谱图(λ=214 nm)

Figure 3. Analytical RP-HPLC chromatogram of two-step oxidative folding process of peptide 2 (A) and peptide 3 (B) (λ=214 nm) (a)~(c) RP-HPLC spectra of the folding solution for peptide 2 at 0, 10 and 45 min. (d) RP-HPLC and ESI-MS spectra of purified peptide 5. The ESI-MS spectrum gave an observed mass of 3109.5 Da (calculated 3109.4 Da, average isotopes). (e)~(f) RP-HPLC spectra of the folding solution for peptide 5 at 5 and 15 min. (g) RP-HPLC and ESI-MS spectra of purified peptide 6. The ESI-MS spectrum gave an observed mass of 2964.7 Da (calculated 2965.5 Da, average isotopes). (h)~(j) RP-HPLC spectra of the folding solution for peptide 3 at 0, 10 and 45 min. (k) RP-HPLC and ESI-MS spectra of purified peptide 7. The spectrum gave an observed mass of 3108.5 Da (calculated 3109.4 Da, average isotopes). (l)~(m) RP-HPLC spectra of the folding solution for peptide 7 at 5 and 15 min. (n) RP-HPLC and ESI-MS spectra of purified peptide 8. The spectrum gave an observed mass of 2964.7 Da (calculated 2965.5 Da, average isotopes). RP-HPLC condition: a linear gradient of 10%~60% buffer B in buffer A over 30 min (10% for 2 min, then 10%~60% for 30 min) on a Vydac C4 column

图4. (A)肽2和(B)肽3的一锅法氧化折叠RP-HPLC色谱图(λ=214 nm)

Figure 4. Analytical RP-HPLC chromatogram of one-pot oxidative folding process of peptide 2 (A) and peptide 3 (B) (λ=214 nm) (a)~(d) RP-HPLC spectra of the folding solution for peptide 2 at 0, 15 min, 18 and 24 h. For peptide 9: the ESI-MS spectrum gave an observed mass of 3109.0 Da (calculated 3109.4 Da, average isotopes). (e)~(f) RP-HPLC spectra of the folding solution for peptide 9 at 30 and 60 min. (g) RP-HPLC and ESI-MS spectra of purified peptide 10. The ESI-MS spectrum gave an observed mass of 2964.8 Da (calculated 2965.5 Da, average isotopes). (h)~(k) RP-HPLC spectra of the folding solution for peptide 3 at 0, 15 min, 18 and 24 h. For peptide 11: the ESI-MS spectrum gave an observed mass of 3108.5 Da (calculated 3109.4 Da, average isotopes). (l)~(m) RP-HPLC spectra of the folding solution for peptide 11 at 30 and 90 min. (n) RP-HPLC and ESI-MS spectra of purified peptide 12. The ESI-MS spectrum gave an observed mass of 2964.8 Da (calculated 2965.5 Da, average isotopes). RP-HPLC condition: a linear gradient of 10%~60% buffer B in buffer A over 30 min (10% for 2 min, then 10%~60% for 30 min) on a Vydac C4 column

图5. (A)肽4、6、8、10和12共进样的分析型RP-HPLC色谱图和ESI-MS质谱图和(B)肽1、4、6、8、10和12的圆二色谱图

Figure 5. (A) Analytical RP-HPLC and ESI-MS spectra of peptides 4, 6, 8, 10 and 12 co-injections and (B) circular dichroism (CD) spectra of peptides 1, 4, 6, 8, 10 and 12 The ESI-MS spectrum gave an observed mass of 2964.8 Da (calculated 2965.5 Da, average isotopes). RP-HPLC condition: a linear gradient of 10%~60% buffer B in buffer A over 30 min (10% for 1 min, then 10%~60% for 30 min) on a Vydac C18 column, λ=214 nm

图6. 肽4、6、8、10和12对TRPV1通道的激动作用

Figure 6. Agonistic effect of peptides 4, 6, 8, 10 and 12 on TRPV1 TRPV1 stably-transfected CHO cells were held at -60 mV and followed by a voltage ramp from –100 mV to +100 mV with 2 s intervals. (A~F) the time courses of TRPV1 currents recorded at +100 mV induced by peptides 1,4,6,8,10,12, and capsaicin (Cap). (G) The normalized currents of peptides 4,6,8,10,12 and linear peptide 1 by capsaicin. n=3~6, data were expresses as mean±SEM, *** p<0.001 vs. capsaicin,###p<0.001 vs. linear peptide 1. ns, no significance

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蜈蚣毒素多肽RhTx的高效化学合成及复性折叠研究

Efficient Synthesis and Oxidative Folding Studies of Centipede Toxin RhTx

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