On May 28, 2020 A-Alpha Bio reported that it has been awarded a National Science Foundation Phase II Small Business Innovation Research (SBIR) grant to continue developing their AlphaSeq platform for the discovery of molecular glues (Press release, A-Alpha Bio, MAY 26, 2020, View Source [SID1234636940]). AlphaSeq is a proprietary drug discovery platform that applies synthetic biology and next generation sequencing to measure up to millions of protein-protein affinities simultaneously by characterizing all interactions between two protein libraries. A-Alpha Bio’s partners use AlphaSeq for antibody development – for example simultaneously optimizing specificity and cross-reactivity. In addition, AlphaSeq will soon be leveraged for the discovery of protein degrading "molecular glues."

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Molecular glues function by physically sticking two proteins together that would not otherwise interact. More specifically, targeted protein degraders redirect an E3 ubiquitin ligase to bind to a target protein, such as an oncogenic or plaque forming protein, and flag it for degradation. Targeted degradation is an attractive strategy for inhibiting otherwise undruggable proteins and has an enormous potential impact for treating cancers, immunological disorders, and neurodegenerative diseases.

The major barrier to molecular glue discovery is the low probability that a small molecule will "glue" together two particular proteins. Not only must the molecule bind to an E3 ubiquitin ligase, but the presence of the bound small molecule must then redirect binding to a target protein intended for degradation.

"Molecular glue discovery is a really hard problem. The only way to solve it is to test a lot E3 ligase-target interactions," said Randolph Lopez, Co-Founder and CTO of A-Alpha Bio. "With probabilities so low, you have to screen more than you would for a typical small-molecule discovery program – and that’s exactly what AlphaSeq allows us to do."

Using AlphaSeq, A-Alpha Bio measures interactions between an entire library of E3 ubiquitin ligases (humans have over 600) and an entire library of target proteins, instead of just one of each. When a drug candidate is tested, AlphaSeq detects interactions between any ligase–target pair. For example, if 100 ligases and 100 targets are included, a single AlphaSeq assay will measure 10,000 potential interactions, all in less than 1 milliliter of volume. Increasing screening throughput by many orders of magnitude, as AlphaSeq enables, is the type of breakthrough required to discover molecular glues and unlock one of the most promising new drug modalities.

During Phase I of their NSF SBIR award, A-Alpha Bio successfully demonstrated feasibility by expressing E3 ubiquitin ligases and target proteins in their AlphaSeq platform and correctly observing protein interactions that are enhanced by existing molecular glues. With continuing support from an NSF SBIR Phase II award, A-Alpha Bio will construct E3 ligase and target libraries, improve assay sensitivity for the detection of weak protein interactions, and develop a high-throughput screening workflow for molecular glue libraries.

"Targeted protein degradation is one of the most exciting and rapidly growing therapeutic modalities," added Randolph. "We are thrilled to have the National Science Foundation’s continued support to develop AlphaSeq for molecular glue discovery."