Serum stable natural peptides designed by mRNA display.
Serum stable natural peptides designed by mRNA display.
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DOI：
10.1038/srep06008
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发表时间：
2014-09-19
影响因子：
4.6
通讯作者：
Roberts RW
中科院分区：
文献类型：
--
作者：
Howell SM;Fiacco SV;Takahashi TT;Jalali-Yazdi F;Millward SW;Hu B;Wang P;Roberts RW
Peptides constructed with the 20 natural amino acids are generally considered to have little therapeutic potential because they are unstable in the presence of proteases and peptidases. However, proteolysis cleavage can be idiosyncratic, and it is possible that natural analogues of functional sequences exist that are highly resistant to cleavage. Here, we explored this idea in the context of peptides that bind to the signaling protein Gαi1. To do this, we used a two-step in vitro selection process to simultaneously select for protease resistance while retaining function–first by degrading the starting library with protease (chymotrypsin), followed by positive selection for binding via mRNA display. Starting from a pool of functional sequences, these experiments revealed peptides with 100–400 fold increases in protease resistance compared to the parental library. Surprisingly, selection for chymotrypsin resistance also resulted in similarly improved stability in human serum (~100 fold). Mechanistically, the decreases in cleavage results from both a lower rate of cleavage (kcat) and a weaker interaction with the protease (Km). Overall, our results demonstrate that the hydrolytic stability of functional, natural peptide sequences can be improved by two orders of magnitude simply by optimizing the primary sequence.
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影响因子：
15
作者：
DADO, GP;GELLMAN, SH
通讯作者：
GELLMAN, SH
影响因子：
2.9
作者：
COMPTON, LA;JOHNSON, WC
通讯作者：
JOHNSON, WC
DOI：
10.1073/pnas.89.20.9367
发表时间：
1992-10-15
影响因子：
11.1
作者：
SIMON, RJ;KANIA, RS;BARTLETT, PA
通讯作者：
BARTLETT, PA
影响因子：
5.7
作者：
Johnston, CA;Willard, FS;Siderovski, DP
通讯作者：
Siderovski, DP
影响因子：
56.9
作者：
HEDSTROM, L;SZILAGYI, L;RUTTER, WJ
通讯作者：
RUTTER, WJ