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    • 4. 发明申请
    • Q4N2NEG2 ENHANCES CFTR ACTIVITY
    • Q4N2NEG2增强CFTR活性
    • WO2003024409A2
    • 2003-03-27
    • PCT/US2002/030094
    • 2002-09-23
    • CASE WESTERN RESERVE UNIVERSITYDAVIS, Pamela, B.MA, JianjieGERKEN, Thomas
    • DAVIS, Pamela, B.MA, JianjieGERKEN, Thomas
    • A61K
    • C07K14/4712A61K38/00
    • Phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) by cyclic AMP- dependent protein kinase (PAK) is essential for opening the CFTR chloride channel. A short segment containing many negatively charged amino acids (817-838, NEG2) within the regulatory (R) domain of CFTR is a critical regulator of the chloride channel activity. An isolated NEG2 polypeptide may be expressed as a separate sequence that stimulates CFTR channel openings at lowe concentrations, but that inhibits CFTR channel openings at higher concentrations. Residues in the NEG2 sequence were substituted to produce a polypeptide that exerts only an activating effect on CFTR. One such polypeptide is the Q4N2NEG2 polypeptide. Exogenous Q4N2NEG2 exerts stimulatory effects on both wild-type and mutant G551D CFTR function, without exhibiting inhibitory activity at any concentration.
    • 通过环AMP-依赖性蛋白激酶(PAK)的囊性纤维化跨膜电导调节因子(CFTR)的磷酸化对于打开CFTR氯离子通道是必不可少的。 在CFTR的调节(R)域内含有许多带负电荷的氨基酸(817-838,NEG2)的短链段是氯通道活性的关键调节剂。 分离的NEG2多肽可以表达为在低浓度刺激CFTR通道开口的单独序列,但是在较高浓度下抑制CFTR通道开口。 取代NEG2序列中的残基以产生对CFTR仅具有活化作用的多肽。 一种这样的多肽是Q4N2NEG2多肽。 外源性Q4N2NEG2对野生型和突变型G551D CFTR功能均有刺激作用,不影响任何浓度的抑制活性。