DARPA Harnessing Enzymatic Activity for Lifesaving Remedies HEALR
HR001120S0052
Grants.gov  https://www.grants.gov/web/grants/view-opportunity.html?oppId=327826
betaSam.gov  https://beta.sam.gov/opp/d778e3c631274d10a3e3f334d629ab8f/view

 strongly encouraged - Proposal Abstract Due Date and Time: August 11, 2020, 4:00 PM ET
Full Proposal Due Date and Time: September 17, 2020, 4:00 PM ET

DARPA is soliciting innovative proposals to develop (1) new therapeutics against Department of Defense (DoD)-priority bacterial threats that leverage host-driven protein degradation or deactivation pathways; and (2) a platform capability to rapidly develop, screen, and optimize therapeutics against emerging bacterial threats.

 By harnessing innate cellular processes, approaches such as proteolysis targeting chimeras (PROTACs) and similar methods can achieve superior outcomes over existing therapies.  PROTACs molecules are referred to as ‘chimeras’ because they are comprised of two ligands connected by a linker; one ligand binds the target protein (i.e., threat-binding ligand) and the second ligand binds a host protein (i.e., host-binding ligand). In the case of PROTACs, the hostbinding ligand binds to an enzyme known as an ubiquitin ligase. When PROTACs molecules bind both the target protein and ubiquitin ligase, the ligase ‘tags’ the target protein for cellular degradation. Existing studies using PROTACs against oncology targets have demonstrated the feasibility of the HEALR approach. PROTACs studies have also shown that their distinct mechanism-of-action (MOA) may be effective at addressing emerging drug resistance. Finally, compared to conventional therapeutics, which must remain persistently bound to the target, HEALR therapeutics have the potential to utilize lower drug doses and increase safety because these MCMs only require transient target binding and can then be ‘recycled’ to act on additional targets.

The three technical areas are: 1. Technical Area 1 (TA1): Microbial Targeting. Develop and demonstrate innovative methods to screen and identify new threat-binding ligands against microbial targets. 2. Technical Area 2 (TA2): Host Machinery Engagement. Develop and demonstrate new strategies to engage cellular processes to degrade or deactivate targets. 3. Technical Area 3 (TA3): Platform Integration. Develop the tools to integrate threat- and host-binding ligands to rapidly construct, optimize, and deliver safe and effective countermeasures against new microbial threats