Effects of serum, enzyme, thiol, and forced degradation on the stabilities of αO‐Conotoxin GeXIVA[1,2] and GeXIVA [1,4],Chemical Biology & Drug Design

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Effects of serum, enzyme, thiol, and forced degradation on the stabilities of αO‐Conotoxin GeXIVA[1,2] and GeXIVA [1,4]
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-01-30 , DOI: 10.1111/cbdd.13167
Shurun Yu _{1,

2,

3} , Yong Wu _{1,

2} , Pan Xu _{1,

2,

3} , Shuai Wang _{1,

2,

3} , Dongting Zhangsun _{1,

2} , Sulan Luo _{1,

2}

Affiliation

αO‐conotoxin GeXIVA, which is a potent antagonist of α9α10 nicotinic acetylcholine receptor (nAChR), is of great interest as a potential analgesic for chronic neuropathic pain. It has three isomers, of which both GeXIVA[1,2] and GeXIVA[1,4] showed similar low nanomolar IC₅₀s in potent blocking rat α9α10 nAChRs. Here, we first reported stabilities of GeXIVA[1,2] and GeXIVA[1,4] in various biochemical circumstances, including human serum, enzymatic degradation, and thiol, which would be the key factors to affect stabilities of the two isomers in vivo. Simultaneously, forced degradation was carried out to evaluate stabilities of the two isomers. GeXIVA[1,2] and GeXIVA[1,4] were unstable when they were incubated in serum and digestive enzymes at 37°C. Their disulfide bond frameworks were easy to be scrambled in GSH and HSA. For different stress conditions, their stabilities were impacted greatly by oxidation, temperature, and alkaline conditions. The results may provide a foundation for storage conditions, structural modification, and pharmaceutical preparation of GeXIVA[1,2] and GeXIVA[1,4].

中文翻译：

血清，酶，硫醇和强制降解对αO-芋螺毒素GeXIVA [1,2]和GeXIVA [1,4]稳定性的影响

αO-芋螺毒素GeXIVA是α9α10烟碱乙酰胆碱受体（nAChR）的有效拮抗剂，作为治疗慢性神经性疼痛的潜在镇痛药引起了广泛的兴趣。它具有三种异构体，其中GeXIVA [1,2]和GeXIVA [1,4]均显示出相似的低纳摩尔IC _50值。有效阻断大鼠α9α10nAChRs。在这里，我们首先报道了GeXIVA [1,2]和GeXIVA [1,4]在各种生物化学环境中的稳定性，包括人血清，酶促降解和硫醇，这将是影响两种异构体在体内稳定性的关键因素。同时，进行强制降解以评估两种异构体的稳定性。当GeXIVA [1,2]和GeXIVA [1,4]在37°C的血清和消化酶中孵育时不稳定。它们的二硫键框架很容易在GSH和HSA中被打乱。对于不同的应力条件，其稳定性会受到氧化，温度和碱性条件的极大影响。该结果可为GeXIVA [1,2]和GeXIVA [1,4]的储存条件，结构修饰和药物制备提供基础。

更新日期：2018-01-30

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