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New article in Nature: building 20,000 new drug candidates

In another major leap forward, researchers at the IPD have just published a revolutionary method for generating brand new protein drugs.

These new drugs – called “mini-protein binders” – combine the specificity of antibodies with the high stability and manufacturability of small molecule drugs. The new de novo designed mini-protein binders were custom built to target either a deadly virus or a potent toxin and were shown to afford protection to mice.

The de novo designed mini-protein binders produced in this study exhibit much greater stability at elevated temperatures and better neutralization than comparable antibodies and natural protein derivatives, have approximately 1/30th of the molecular weight, and are readily chemically synthesizable, which enables the introduction of a wide variety of chemical functionality. Probably as a result of their small size and very high stability, they elicit little immune response. The best of the flu-targeting designs provides prophylactic and therapeutic protection against influenza infection in mouse models with a potency rivalling or surpassing that of antibodies.

This new method of drug development relies on the integration of computer modeling and laboratory testing to rapidly generate and evaluate tens of thousands of potential mini-protein binders with varying shapes. This unprecedented scale of de novo protein design was made possible by recent advances in both the Rosetta software suite and DNA manufacturing. Using this method, mini-protein binders can be rapidly programmed to target a range of proteins, including other viruses, toxins, or even tumor-specific markers.

Artist impression of designed mini-protein binders targeting Influenza hemagglutinin to effectively bind and neutralize the virus. Cognition Studio, Daniel-Adriano Silva, Lance Stewart

Read the full research article here:

Massively parallel de novo protein design for targeted therapeutics PDF

Aaron Chevalier*, Daniel-Adriano Silva*, Gabriel J. Rocklin*, Derrick R. Hicks, Renan Vergara, Patience Murapa, Steffen M. Bernard, Lu Zhang, Kwok-Ho Lam, Guorui Yao, Christopher D. Bahl, Shin-Ichiro Miyashita, Inna Goreshnik, James T. Fuller, Merika T. Koday, Cody M. Jenkins, Tom Colvin, Lauren Carter, Alan Bohn, Cassie M. Bryan, D. Alejandro Fernández-Velasco, Lance Stewart, Min Dong, Xuhui Huang, Rongsheng Jin, Ian A. Wilson, Deborah H. Fuller& David Baker.