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Bacterial cGAS-like Enzymes to Enable Immunotherapies Design

Enzymes may be used for large-scale synthesis or production of described and novel nucleotide second messengers.

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Project Overview

  • Nucleotide second messenger signals allow cells to amplify stimuli, and rapidly control downstream responses. Such signalling molecules like cyclic dinucleotides (CDNs) were first identified in bacteria but have since been illustrated to be highly important for signalling in humans.
  • Most recently, synthetic CDN analogues have emerged as promising lead compounds for immune modulation and cancer immunotherapy.
  • Using a bacterial signaling screen, Dana-Farber scientists discovered a large family of cGAS/DncV-like nucleotidyltransferases (CD-NTases) that synthesize a diverse range of CDNs with potential applications in biotechnology and as therapeutics.
  • This technology is available for licensing.

Technology

The understanding of the true scope of immune responses to bacterial second messenger products is limited and restricted to cyclic dipurine molecules. Accordingly, there remains a great need to understand the diversity of the bacterial second messenger products and their functions in modulating immune responses to design better therapeutics. 

Research from the laboratory of Philip Kranzusch, PhD revealed a new family of bacterial nucleotidyltransferases, termed cGAS/DncV-like nucleotidyltranserase (CD-NTase) family enzymes, that synthesize linear or cyclic oligonucleotides. Their data shows that bacterial CD-NTases are widespread and synthesize diverse CDNs. Specifically, the oligonucleotide products of CD-NTases include novel cyclic di-pyrimidine and cyclic purine-pyrimidine hybrid molecules, cyclic trinucleotides, and known molecules such as cyclic GMP-AMP. 

Different CDNs and related nucleotide signals made by prokaryotic CD-NTases may possibly either activate or block innate immunity and metabolic processes. This offers a potentially valuable new reservoir of compounds for use in biotechnology and therapeutic applications.

Further Details: 

Whiteley, A.T., Eaglesham, J.B., de Oliveira Mann, C.C. et al. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature 567, 194–199 (2019).

Team Members: Philip Kranzusch, PhD, John Mekalanos, PhD, James Eaglesham, PhD, Aaron Whiteley, PhD

Applications

  • These here may be used for large-scale synthesis or production of described and otherwise novel nucleotide second messengers, including 3’3′ cyclic UMP–AMP, 3’3′ cyclic AMP–GMP, and 3’3’3′ cyclic AMP-AMPGMP. 
  • CDNs and their derivatives have emerged as lead compounds for many therapeutic uses. For example, they have been found to enhance checkpoint blockade immunotherapy of cancer and as adjuvants for vaccine immunogens. 
  • Compounds described here are potentially partially mimic advantageous effects of microbiome on chronic disease conditions and effectiveness of therapies. 

Opportunities

Dana-Farber is seeking a license or sponsored research.

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Team Members