DNA Nanoswitches: “Lab-on-a-Molecule” Drug Discovery

The Problem

Current approaches in compound screening are often limited in either throughput – the simultaneous investigation of large numbers of chemical or biological compounds for a specific biological target –  or in the ability to screen for the complex ways disease-relevant molecules can be functionally affected by drugs. This can make it challenging to discover new therapeutics that modulate proteins’ activities, hindering the development of treatments for many diseases.

Our Solution

Using DNA nanoswitch technology developed in Wesley Wong’s group at the Wyss Institute, Boston Children’s Hospital, and Harvard Medical School, the Lab-on-a-Molecule project has created a platform that enables high-throughput, low-cost screening of libraries composed of small molecules, biologics, peptides, and other types of compounds to discover novel drug candidates based on how they affect the function of disease-relevant proteins. Such effects can include the stabilization of a target protein’s desired conformation (allosteric modulator), or the increased or decreased interaction of a target protein with a binding partner in a downstream pathway, such as a receptor with an associated signal-transducing protein.

DNA nanoswitches are nanoscale devices that can report the interaction patterns of attached components through changes in their spatial arrangements. These devices are long, linear DNA molecules that serve as programmable scaffolds to which binding partners, such as proteins or small molecules, can be attached. Association of these binding partners leads to the formation of loops, which can be identified and separated out by gel electrophoresis. For example, a DNA nanoswitch could be created that contains both a disease-related protein and a downstream binding partner. Addition of a stabilizing therapeutic candidate would cause these two proteins to bind strongly, causing the nanoswitch to form a loop. The programmability of DNA nanoswitches enables precise control over pathway components at the single molecule level, including setting defined target and drug quantities (stoichiometries), and local concentrations.

Future Impact

Recognizing the Lab-on-a-Molecule project’s potential for innovating the drug discovery process and identifying drug candidates for thus far untreatable or extremely difficult-to-treat diseases, the Wyss Institute named it a 2022 Validation Project. In 2023, Northpond Labs, the research and development-focused affiliate of venture capital firm Northpond Ventures, selected the Lab-on-a-Molecule project as a Northpond Labs project and is providing additional support to help de-risk the team’s technology and drive business development strategy towards commercialization.

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