Siobhan Malany

Activates CXCR4 in a Non-Allosteric Manner, Facilitating Hematopoietic Cell Recruitment to Wound Sites and Promoting Tissue Repair

These thiadiazine-based small molecules promote wound healing and tissue repair in diabetic patients. Diabetes incidence has reached epidemic proportions in the United States and globally, and impaired diabetic wound healing is a growing problem. In severe cases, it triggers a chronic inflammatory state, leading to the development of vascular disease and impaired wound healing. Lower extremity ulcers are the leading cause of hospitalizations and amputations among diabetic patients, underscoring the critical need for therapeutics effectively promoting wound healing. The development of such therapeutics has the potential to enhance patient outcomes and reduce healthcare expenditures, estimated at approximately $1.5 billion annually.

Diabetic wounds lack the expression of SDF-1a (stromal-derived factor-1a), which is essential for controlled wound healing. SDF-1a canonically binds to CXC chemokine receptor type 4 (CXCR4), serving as a signal to recruit hematopoietic cells to the location of tissue injury and promote tissue repair. Reduced expression of SDF-1a in diabetic wounds signifies its contribution to wound healing and depicts the CXCR4 receptor as a target for diabetic wound therapeutic development.

Researchers at the University of Florida have synthesized small molecule CXCR4 agonists to promote wound healing and tissue repair in diabetic patients. By binding to and activating the CXCR4 receptor, the agonists trigger hematopoietic cell recruitment to wound sites and necessary protein production to stimulate tissue repair.

Application

Binds to and activates CXCR4 to recruit hematopoietic cells to wound sites and promote diabetic wound healing

Advantages

• Activates CXCR4 receptors, recruiting hematopoietic cells to the diabetic wound site and promoting healing
• Binding to CXCR4 receptors does not competitively displace interactions with the endogenous ligand SDF-1a, enabling a synergistic effect between SDF-1a and the compounds
• Administration routes can include oral, topical, parenteral, inhalation, spray, sublingual, transdermal, rectal, and ophthalmic solution, enabling better dosage designs per patient requirements

Technology

University of Florida researchers have formulated small molecule agonists of the CXC chemokine receptor type 4 (CXCR4) to improve wound healing in diabetic patients by recruiting hematopoietic cells to wound sites. The CXC chemokine SDF-1a is a vital regulator of the recruitment of hematopoietic cells to injury locations to promote tissue repair through binding and activating the CXR4 receptor. However, diabetic wounds show decreased expression of SDF-1a, leading to impaired wound healing. These thiadiazine-based small molecules bind to and activate the CXCR4 receptor in an allosteric manner to recapitulate flawed recruitment of hematopoietic cells and collagen I production in wound sites and angiogenesis. The allosteric binding of these compounds to CXCR4 leads to no competition with the endogenous ligand SDF-1a, enabling synergistic effects. This system has shown significant improvements in the rate of wound closure in mouse models of diabetic wounds, decreasing wound healing time and potentially increasing patient outcomes.