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저자： 업로드：2015-08-18 조회수：
Scientists at the Scripps Research Institute (TSRI) have devised an improved method for building proteins into larger proteins such as antibodies. The new technique mimics evolution by generating millions of possible junction segments between the inserted protein and its antibody host, selecting the rare ones that allow the inserted protein to fold and function normally. The technique should speed the development of drug and diagnostic compounds that would not have been possible otherwise, including powerful hormone-based therapies.
"Unlike prior approaches to this design problem, ours is a selection-based method, and it's hard to beat this approach, with its ability to harness the power of very large numbers," said senior investigator Richard A. Lerner, Ph.D., the Lita Annenberg Hazen Professor of Immunochemistry at TSRI.
The technique is general enough so it could have many clinical and scientific applications, for example, determining why proteins fold as they do. "It effectively enables you to put a measuring device in the middle of a protein to determine if it's folded properly," continued Dr. Lerner.
The study ("A General Method for Insertion of Functional Proteins Within Proteins Via Combinatorial Selection of Permissive Junctions"), a collaboration between Dr. Lerner's laboratory at TSRI, the laboratory of Jeffrey M. Friedman, M.D., Ph.D., at Rockefeller University and the TSRI groups of Ian A. Wilson and Patrick R. Griffin, appears in Chemistry and Biology.
In one proof-of-principle demonstration, the team edited the genetic code of a standard human antibody to replace one of its target-grappling elements—a structure that normally would bind to a virus, for example—with the protein leptin. First identified by Dr. Friedman in 1994 as a satiety hormone that switches off hunger, leptin initially failed as an obesity therapy, as obese people tend to be insensitive to leptin rather than leptin-deficient. However, the hormone has drawn renewed interest in recent years as a possible basis for treating obesity, in conjunction with leptin-sensitizing compounds, and also diabetes.
Leptin on its own and in an unmodified state isn't ideal as a therapy because it doesn't last long in the bloodstream. "The kidneys and other organs clear it very rapidly," said Yingjie Peng, a staff scientist in the Lerner laboratory who was first author of the study with Wenwen Zeng of Friedman's lab at Rockefeller. "But it could last much longer if it were part of a larger structure such as an antibody."
The major challenge for Dr. Lerner, Peng and their colleagues was to design leptin into an antibody in such a way that it would fold up into a functional structure despite being bound to its host protein at either end.
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