Abstract
The design, synthesis and screening of diversity-oriented peptide libraries using a “libraries from libraries” strategy for the development of inhibitors of α1-antitrypsin deficiency are described. The major buttress of the biochemical approach presented here is the use of well-established solid-phase split-and-mix method for the generation of mixture-based libraries. The combinatorial technique iterative deconvolution was employed for library screening. While molecular diversity is the general consideration of combinatorial libraries, exquisite design through systematic screening of small individual libraries is a prerequisite for effective library screening and can avoid potential problems in some cases. This review will also illustrate how large peptide libraries were designed, as well as how a conformation-sensitive assay was developed based on the mechanism of the conformational disease. Finally, the combinatorially selected peptide inhibitor capable of blocking abnormal protein aggregation will be characterized by biophysical, cellular and computational methods.
Highlights
Combinatorial chemistry in drug discovery represents an amalgamation of chemistry and biology, which generally involves the practice of chemical synthetic methods and coupled with biological screening assays
Given that the inhibitory mechanism and pathogenic polymerization of serpins are both conducted by the incorporation of reactive center loop (RCL), it appears that RCL peptides can compete with endogenous RCL at the same binding site and intervene in the propagation of polymerization
NF-jB, IL-6, IL-8, and RGS16 and calnexin were abrogated effectively by the peptide, which means the endoplasmic reticulum (ER) stress response due to Z-AT aggregation was alleviated. These results suggest that the peptide is highly effective in blocking the pathogenic cellular activation associated with Z-AT aggregation and ER stress
Summary
Combinatorial chemistry in drug discovery represents an amalgamation of chemistry and biology, which generally involves the practice of chemical synthetic methods and coupled with biological screening assays It allows rapid preparation and high-throughput screening of compound libraries for the identification of drug candidates or optimization of lead compounds. Peptide libraries are a key research tool for the search of bioactive compounds by screening large numbers (tens of thousands or even billions) of peptides that is not practically attainable by traditional chemical approach These synthetic libraries can be prepared as either mixtures or sets of individual peptides by using tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc) SPPS methods.
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