Key Dates

Related Announcements

• October 31, 2023- Notice of Early Expiration of "Notice of Special Interest (NOSI): Using Targeted Degradation of Protein and non-Protein Targets for the Development of Novel Anti-Infectives". See Notice NOT-AI-23-063.
• July 12, 2023 -- PHS 2023-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed). See NOFO PA-23-230
• July 12, 2023 - PHS 2023-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed). See NOFO PA-23-232
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.
• May 7, 2020 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed).  See NOFO PA-20-200
• May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).  See NOFO PA-20-185

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to invite applications for research on the use of targeted protein and nonprotein degradation (e.g., RNA) as it relates to the development of anti-infective strategies against viral, bacterial, parasitic, and fungal pathogens and/or their toxins (e.g., Lethal and Edema Toxins of Bacillus anthracis). Both novel monofunctional (e.g., Molecular Glues) and hetero-bi/tri-functional (e.g., PROTAC or PROTAC-like) strategies will be considered.

Background

Targeted degradation, including targeted protein degradation (TPD), is a rapidly growing technology which shows promise as a new paradigm in effective medical countermeasures (MCMs) to target the increased global need against diverse and resistant infectious agents.  Specifically, TPD leverages a cell’s natural proteostasis mechanisms to promote the specific degradation of a molecule of interest, as a means to eliminate an integral component of a biological process that contributes to an infection or disease.  In 2001, a TPD chimera called protac-1 was shown to be capable of degrading a target protein, methionine aminopeptidase-2, opening up the possibility of leveraging this approach against other protein targets involved in disease conditions.  Since 2001, there have been numerous TPD drug candidates in various stages of development, but those that target infectious agents are quite limited. New evidence now shows that TPD technology can likewise be harnessed toward the development of anti-infectives. For example, one of the most recent areas of development of targeted degradation against infectious agents has been the development of degraders which target viral-specific proteins during replication as well as “host-directed approaches”. Recent data also suggest this technology can be advanced against pathogenic bacteria, fungi, and toxins with development of appropriate binders to the respective protein, or nonprotein, target of interest and a proteolytic mechanism, with subsequent degradation of the target protein. Another advantage of targeted degradation is its potential to address the increasing specter of multi-drug resistance of pathogenic agents which are intractable against current standards of care, for example, methicillin resistant Staphylococcus aureus (MRSA). Thus, this NOSI serves to support the discovery and development of degrader technologies against infectious agents.

Research Objectives

To support discovery and development of compounds that promote targeted protein degradation (TPD) and, where appropriate, non-protein targets (e.g., RNA), of viral, bacterial, parasitic, or fungal pathogen components including targeting mechanisms integral for the replication, growth, survival or virulence of a pathogen including toxin or toxin-related targets (e.g., toxin receptors) as novel anti-infectives. Applications could include but are not limited to the following basic and translational topics:

• Identify additional pathogen and host proteins/enzymes that can be exploited in the development of novel degraders.
• Generate, characterize, and optimize degrader(s) that stimulate the degradation of a specific pathogen, toxin, or host target(s).
• Develop and optimize relevant assays that allow for the assessment of the functionality of the degraders to degrade infectious targets.
• Determine the substrate specificity and kinetics of degrader interactions with the pathogen or host target, and/or to the degradative machinery components if applicable.
• Determine rate limiting steps and factors that lead to the formation of a productive degradative complex to assist rational design and synthesis of effective degraders.
• Discover and develop highly selective ligands with high affinity to pathogen targets and host machinery components using ligand discovery technologies and relevant animal models or assays.
• Improve drug-like properties of degraders (e.g., physicochemical properties, pharmacokinetic profiles, cell permeability, solubility, oral bioavailability, etc.) through Structure-Activity Relationship (SAR) studies to improve therapeutic benefit as demonstrated/proof of concept in a small animal model.

Applications proposing any of the following will NOT be supported under this NOSI:

• Approaches that utilize gene-editing or gene knock-out/knock-in level, e.g., CRISPR-Cas9, or gene knock-down, e.g., RNA interference (RNAi).
• Technologies that use targeted protein inactivation (TPI), which require adding an aminoacidic signal sequence (tag) to the protein of interest (POI).
• Method(s) that directly alter or target the genome or epigenome of the host including those due to unforeseen off-target effects. 
   

Application and Submission Information

This notice applies to due dates on or after January 5, 2024, and subsequent receipt dates through July 16, 2026.

Submit applications for this initiative using one of the following notices of funding opportunities (NOFOs) or any reissues of these opportunities through the expiration date of this notice.

• PA-20-185 – NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-195 – NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
• PA-20-200 – NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
• PA-23-232 – PHS 2023-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed).
• PA-23-230 – PHS 2023-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed).  

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AI-23-076” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Raymond M. Slay, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-325-8578
Email: slayrm@niaid.nih.gov