Genetic Engineering & Biotechnology News

JUL 2017

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24 | JULY 2017 | GENengnews.com | Genetic Engineering & Biotechnology News See Peptide-Based Therapeutics on page 26 Protein Engineering. Since then, Dr. Winter, as cofounder and director of Bicycle Therapeutics, has participated in the development of structures that offer an intriguing combina- tion of chemical diversity, compactness, and specificity for significant drug targets. Bicycle creates its bicyclic peptides through phage display, a well-known technique in the monoclonal antibody (mAb) marketplace. A small-molecule crosslinker zips the "bicycle" structure together by covalently binding to three amino acids to form a compact, tightly constrained molecule. "The idea was to duplicate the activity of a mAb with the absolute mini- mum number of amino acid residues," Nick Keen, Ph.D., chief scientific officer of Bicycle Therapeutics, tells GEN. He refers to this idea—Dr. Winter's discovery—as a "stroke of genius." Bacteriophage display is known for creating immense chemical diversity, with each virus expressing a unique pep- tide sequence that is capable of being crosslinked in situ. Phage assemblies showing affinity for molecular targets un- dergo affinity-based selection analogous to a typical mAb discovery program. Synthesizing and screening even tiny subsets of phage- displayed peptide libraries—Bicycle's contain many billions of unique structures—would take forever using manual methods. Bicycle peptides that bind are further optimized through affinity maturation. The process involves identifying amino acids responsible for target binding and creating sublibraries con- taining various combinations and sequences of those residues. "We can get down to very potent binders in a matter of weeks using evolutionary biol- ogy, and without doing any syn- thetic chemistry," says Dr. Keen. "We've stopped worrying if targets are druggable. It takes just weeks to run the screen to identify binders, which is less time than it would take to perform molecular modeling." Bicycle gets down to subnanomolar binding affinities rapidly, with antibody-like strength and selectivity. This kind of binding sometimes occurs right off the bat, but even when it doesn't, scientists are able to develop useful struc- ture-activity relationships from the binding data. When ad- vantageous, unnatural amino acids can be swapped into the bicyclic peptides. "We joke that bacteriophages are the hardest working chemists on earth. We don't pay them much, and they work overnight without grumbling," Dr. Keen jokes. After expression and crosslinking, the structures are in the 1.5 kDa molecular weight range. That is larger than a typi- cal small-molecule nonpeptide drug, but given the geometric constraints, these structures do, in fact, behave in vivo like classical pharmaceuticals. Doses are in the milligram range, for example, but Dr. Keen notes that the dose depends on the pharmacokinetics and distribution. Bicycles penetrate tumors much more easily than much larger antibodies and have systemic half-lives of minutes to a few hours. These characteristics are useful for drugs requiring a high concentration within diseased tissue and low systemic toxicity. The Driver: Diabetes Much innovation in peptide half-life extension has oc- curred by way of structural modifications of glucagon-like peptide 1 (GLP-1) products, which typically are used to treat type 2 diabetes. The natural hormone GLP-1 is released by the intestine to stimulate insulin release in response to food consumption. Type 2 diabetics respond well to GLP-1, but because the molecule's plasma half-life is about two minutes, chemical modifications to improve the molecule's pharma- cokinetics have been a top priority for drug manufacturers. Novo Nordisk has been working with acylated peptides for two decades. Its first success in this category was acylated insulin, which enabled once-daily dosing and opened the door to chemical modification and half-life extension of pep- tides. Subsequently, GLP-1 emerged as a potential diabetes treatment as exenatide, an acylated product with a half-life of less than two hours. Novo further improved on this idea by developing two additional GLP-1 analogues: liraglutide, which incorporates an altered half-life-mediating sidechain, and semaglutide, which provides improved albumin binding. Both liraglutide, which permits once-daily dosing, and sema- glutide, which provides basal insulin release for an entire week, are dosed in the 1–2 mg range. "It took some interesting medicinal chemistry to modify the GLP-1 molecule into those products," says Christopher Rhodes, Ph.D., CEO of Drug Delivery Experts, who was not involved in Novo's reasearch on GLP-1. Acendis, a German company, and U.S.-based Prolynx Optimizing the Delivery of Peptide-Based Therapeutics Bioprocessing Feature Bicycle Therapeutics develops bicyclic peptides that provide antibody-like target specificity and high affinity. The company can generates phage display libraries comprising more than 10 15 unique bicyclic peptides. To screen the peptides, the company uses multiple iterative rounds of phage selection combined with identification of bicyclic peptides using sequencing and a parallel functional assay to determine binding and affinity. Continued from page 1 Having affinity regions measuring just three to nine amino acids, typically, bicycles qualify as small-molecule drugs, as far as regulators are concerned.

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