New Chapter for DNA-Encoded Chemical Libraries

A new approach to finding drug candidates for fighting cancers can drastically cut the time and money needed to evaluate millions of them.

by Poornima Apte
August 27, 2018

Imagine a laboratory that has a library of 35 million different chemical compounds. Hidden within them are is the key to a potentially life-saving drug.

The traditional method for testing the efficacy of those compounds is to screen each one serially, a time-consuming and expensive process. Now, a team led by Dario Neri of ETH Zurich has developed a way to do high-throughput screening of large batches of promising compounds at the same time. Neri’s ultimate goal is to create very large DNA-encoded chemical library (DECL) of small molecule compounds and use it to discover combinations of compounds that mimic the way receptors on an antibody target specific cells and proteins.

So far, the researchers have shown they can produce specific binders for a variety of proteins, including carbonic anhydrase IX, horseradish peroxidase, tankyrase 1, human serum albumin, alpha-1 acid glycoprotein, calmodulin, prostate-specific antigen, and tumour necrosis factor.

At its most basic, the process works by tagging each chemical compound with a DNA strand and testing groups of compounds against biological targets (such as tumors) in batches. After washing out the reactor, only the compounds that attached to the targets will remain. Researchers then use a combination of the polymerase chain reaction (PCR) and high-throughput sequencing to produce enough of those promising candidates to identify.

By testing enormous numbers of compounds at a time, Neri can hone in on promising candidates faster and at less expense. The method has potential uses in the discovery of novel drugs and medications to fight cancer.

Using DECL to simulate antibodies

Neri and Harvard University’s David Liu have been pushing their high-throughput screening work since the early 2000s. In 2009, Neri and ETH Zurich senior scientist Jörg Scheuermann coded 4,000 molecules and found the first small molecule that might help treat rheumatoid arthritis.

Neri and Scheuermann’s latest DECL work focuses on using combinations of three small DNA-encoded molecules that create “hooks” and “handles.” By starting with hundreds or thousands of individual molecules and combining them randomly, the researchers hope to produce a few hooks and handles that bind perfectly onto a protein in a cell, a bacterium, or a tumor.

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Neri and Scheuermann start by connecting the three small molecules to a stable ring-shaped structure developed by Manfred Mutter from the University of Lausanne. They also attach a small molecule drug, perhaps a cancer-fighting medicine, to the ring. When the artificial antibody recognizes and latches onto the tumor, it releases the medication inside the cell in a highly targeted and localized approach.

The small molecule approach is one of the things that sets this DECL approach apart.

“A solid tumor has a higher pressure inside than the outside so it’s really hard to penetrate it in the first place,” Scheuermann says. “Having something big makes it worse. Smaller molecules can penetrate these tumors much better than big molecules like antibodies.”

Small molecules weight about 150 times less than a typical antibody. But smaller molecules have their challenges, too. Most importantly, they lack the stickiness of larger molecules.

“The drawback of small molecules is that the tightness of binding is usually not as good as antibodies, which contain handles for binding,” he says. “Normally, the compounds tested by DNA-encoded chemical libraries are more compact, but we wanted to mimic antibodies that span a larger surface that can yield tighter binding.”

By spacing his small molecules along a ring, Scheuermann hopes to achieve a good compromise between the penetrating abilities of small molecules and the stickiness of antibodies. The key advantage to such DECL testing is that it quickly and efficiently narrows down the field of contestants, saving time and money.

“This is an opportunity for pharma companies to find, more easily than in the past, chemical entities which they can bring forward into active drug development,” Scheuermann adds.

Poornima Apte is an independent technology writer.

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