Selective PAD2 Inhibitors for Neuroprotection in Traumatic Brain Injury

SHORT DESCRIPTION

Novel PAD2-selective inhibitor platform targeting neuroinflammation to support both acute neuroprotection and long-term functional recovery as a first-in-class treatment of traumatic brain injury.

• Hasan Alam*
  • Northwestern University Feinberg School of Medicine, Department of Surgery (Trauma and Critical Care Division)
• Zaiba Shafik Dawood
  • Northwestern University Feinberg School of Medicine, Department of Surgery (Trauma and Critical Care Division)
• Yongqing Li
  • University of Michigan Medical School, Department of Surgery
• Paul Thompson
  • UMass Chan Medical School, Department of Biochemistry and Molecular Biotechnology
• Bowen Wang
  • Northwestern University Feinberg School of Medicine, Department of Surgery

NU Tech ID  NU 2025-172

IP STATUS

US Patent Provisional Application Filed (63/843,974)

DEVELOPMENT STAGE

TRL-5 Prototype Validated in Relevant Environment: Demonstrated efficacy in murine and porcine models of TBI.

BACKGROUND

Traumatic brain injury (TBI) occurs when a serious blow to the head damages the brain. TBI can occur from car accidents, falls, and combat, and can result in lasting effects such as memory loss, depression, brain fog, and cognitive impairment. Current treatments remain largely supportive and are directed at stabilizing the patient and minimizing further secondary insults (e.g., hypoxia, hypotension), but none directly mitigate the molecular and cellular cascades that follow the primary injury. These approaches are limited by high costs, delays in interventions, and lack of targeted mechanisms. Moreover, currently there are no drugs that protect the brain or promote recovery after TBI, underscoring the urgent need for a pharmacologic solution. This lack of effective treatment options for TBI is especially concerning given the major burden it imposes on both civilian and military populations. Therefore, there is a critical need for interventions that enhance recovery and reduce long-term impairment for TBI patients.

ABSTRACT

A team of Northwestern researchers and collaborators have developed a novel series of first-in-class selective protein arginine deiminase 2 (PAD2) inhibitors designed to interrupt the neuroinflammatory processes following traumatic brain injury. These small molecule inhibitors directly target PAD2 activity, which contributes to brain damage post-injury, to reduce and prevent secondary brain damage and silence neuroinflammatory cascade pathways. The lead compound, AFM41a, has already demonstrated strong potential to protect the brain and improve long-term recovery in TBI mice models, reducing lesion size and improving both acute and long-term functional outcomes. Not only do PAD2 inhibitors offer a mechanistic advancement over existing supportive care, but also have multiple applications in preventing TBI in both hospital, rehabilitation, and combat settings. These small molecule PAD2 inhibitors open an avenue toward the first disease-modifying therapy for TBI and have potential to treat other neurological disorders marked by neuroinflammation such as stroke and neurodegenerative diseases.

APPLICATIONS

• Acute neuroprotection in TBI patients: Provides rapid intervention to reduce brain lesion and edema.
• Reduction of neuroinflammation: Targets key inflammatory cascades following brain injury.
• Field-stable therapy for military trauma care: Enables early administration in combat or austere environments.
• Management of chronic neurological sequelae: Offers potential long-term benefits for cognitive recovery.
• Broad application: potential for use in treatment of other neuroinflammatory or neurodegenerative diseases.

ADVANTAGES

• Novel first-in-class compound targeting a unique pathway to treat TBI
• Targets disease mechanism: Inhibits PAD2 to curb neuroinflammatory cascades effectively.
• Enhances recovery: Demonstrates improved outcomes in both acute and long-term settings.
• Minimizes off-target effects: Selectively modulates PAD2 activity to improve safety profile.
• Provides extended treatment windows: Enables intervention in both immediate and delayed phases post-injury

PUBLICATIONS

• Muth A et al., Development of a Selective Inhibitor of Protein Arginine Deiminase 2, J Med Chem, 2017 Apr 13;60(7):3198-3211.
• Dawood ZS et al., Role of peptidylarginine deiminase 2 in a murine model of traumatic brain injury. J Trauma Acute Care Surg. 2026 Feb 1;100(2):189-197.

CATEGORY/INDUSTRY PIPELINE

Therapeutics

KEYWORDS

Protein Arginine Deiminase 2, PAD2 inhibitor, traumatic brain injury, TBI therapeutics, neuroinflammation, neuroprotection, small molecule, preclinical, drug development, glial activation, cognitive recovery, selective inhibitor, translational medicine