Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4

  • Sci Rep. 2023 Feb 23;13(1):3189. doi: 10.1038/s41598-023-30246-2.
Chandru Gajendran  1 ,  Shoichi Fukui  2  3 ,  Naveen M Sadhu  1 ,  Mohammed Zainuddin  1 ,  Sridharan Rajagopal  1 ,  Ramachandraiah Gosu  1 ,  Sarah Gutch  2 ,  Saeko Fukui  2 ,  Casey E Sheehy  2 ,  Long Chu  2 ,  Santosh Vishwakarma  4 ,  D A Jeyaraj  4 ,  Gurulingappa Hallur  4 ,  Denisa D Wagner  2  3  5 ,  Dhanalakshmi Sivanandhan  6
Affiliations
  • 1. Jubilant Therapeutics Inc., Bedminster, NJ, USA.
  • 2. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 3. Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
  • 4. Jubilant Biosys Limited, Bangalore, India.
  • 5. Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02125, USA.
  • 6. Jubilant Therapeutics Inc., Bedminster, NJ, USA. [email protected].
PMID: 36823444 DOI: 10.1038/s41598-023-30246-2
Abstract

Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. Further, studies with PAD4 - deficient mice have shown that PAD4 deficiency does not lead to increased Infection or immune suppression, which makes PAD4 an attractive therapeutic target for auto-immune and inflammatory diseases. PAD4 has critical enzymatic role of promoting chromatin decondensation and neutrophil extracellular traps (NETs) formation that is associated with a number of immune-mediated pathological conditions. Here, we present a non-covalent PAD4 inhibitor JBI-589 with high PAD4 isoform selectivity and delineated its binding mode at 2.88 Å resolution by X-ray crystallography. We confirmed its effectiveness in inhibiting NET formation in vitro. Additionally, by using two mouse arthritis models for human rheumatoid arthritis (RA), the well-known disease associated with PAD4 clinically, we established its efficacy in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.

Products