BIOCHEMICAL STRATEGY TO AVERT MICROBIAL DRUG RESISTANCE - PROJECT SUMMARY/ABSTRACT THE GOAL OF THE PROPOSED…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
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ASST_NON_R21AI171663_075 · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · Department of Health and Human Services
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- Assistance award identifier
- ASST_NON_R21AI171663_075
- FAIN
- R21AI171663
- Recipient
- MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.855
- Total obligated
- $155,100
- Period
- Jun 14, 2022 – May 31, 2024
- Fiscal year
- 2023
- Place of performance state
- MA
- Source file
- FY2023_All_Assistance_Full_20261006.zip
Description
BIOCHEMICAL STRATEGY TO AVERT MICROBIAL DRUG RESISTANCE - PROJECT SUMMARY/ABSTRACT THE GOAL OF THE PROPOSED RESEARCH IS TO DEVELOP A GENERALIZABLE ANTIMICROBIAL STRATEGY THAT AVERTS THE ONSET OF RESISTANCE. THE PROPOSED ANTIVIRAL AGENT HAS A MECHANISM OF ACTION THAT RELIES ON THE FUNCTION OF A PATHOGENIC PROTEIN RATHER THAN ITS INHIBITION. SPECIFICALLY, THE AGENT IS A CYTOTOXIC VARIANT OF A HUMAN ENZYME, RIBONUCLEASE 1 (RNASE 1), THAT IS CLOAKED AND THUS INACTIVE AS A CATALYST. THE CLOAK IS REMOVABLE ONLY BY A PATHOGENIC PROTEASE THAT IS ESSENTIAL FOR THE LIFECYCLE OF THE PATHOGEN. SARS-COV-2 WILL SERVE AS A MODEL PATHOGEN IN THE STUDY. THE GOAL WILL BE ATTAINED BY (1) IDENTIFYING AN OPTIMAL AMINO ACID SEQUENCE THAT IS CLEAVED BY THE 3CLPRO PROTEASE OF SARS-COV-2 BUT NOT BY ENDOGENOUS HUMAN PROTEASES, (2) USING THAT SEQUENCE AND INTEIN-MEDIATED CIS- SPLICING TO CREATE A CYCLIC RNASE 1 ZYMOGEN, AND (3) DEMONSTRATING THE ABILITY OF THE ZYMOGEN TO KILL HUMAN LUNG CELLS THAT EXPRESS 3CLPRO AND THAT ARE INFECTED BY SARS-COV-2. BECAUSE THE ACTIVATED ZYMOGEN CAN ALSO DESTROY THE GENOME OF AN RNA VIRUS LIKE SARS-COV-2, IT COULD ERADICATE THE VIRAL RESERVOIR IN PATIENTS. A NOTABLE FEATURE OF THE STRATEGY IS ITS MODULARITY: THE PROTEASE-CLEAVAGE SEQUENCE IS A CASSETTE THAT CAN BE ALTERED TO MATCH THE SPECIFICITY OF PATHOGENIC PROTEASES FOR THE TREATMENT OF OTHER INFECTIOUS DISEASES.