Chronic wounds affect a large percentage of the population world-wide and cause significant morbidity. Unfortunately, efficient compounds for the treatment of chronic wounds are as yet not available. Endothelial dysfunction, which is at least in part a result of compromised nitric oxide production and concomitant reduction in cGMP levels, is a major pathological feature of chronic wounds. Therefore, Topatur designed and synthetized a compound with unique dual-acting activity (TOP-N53), acting as nitric oxide donor and phosphodiesterase 5 ihibitor, and applied it locally to full-thickness skin wounds in healthy and healing-impaired diabetic mice.
Under the title "A dual-acting nitric oxide donor and phosphodiesterase 5 inhibitor promotes wound healing in normal and diabetic mice" (JID-2019-0913.R1) the Journal of Investigative Dermatology accepted a manuscript from a team of scientist from ETH Zürich and Topadur for publication.
TOP-N53 promoted keratinocyte proliferation, angiogenesis and collagen maturation in healthy mice without accelerating the wound inflammatory response or scar formation. Most importantly, it partially rescued the healing impairment of genetically diabetic db/db mice by stimulating re-epithelialization and granulation tissue formation, including angiogenesis. In vitro studies with human and murine primary cells showed a positive effect of TOP-N53 on keratinocyte and fibroblast migration, keratinocyte proliferation, as well as endothelial cell migration and tube formation. These results demonstrate a remarkable healing-promoting activitiy of TOP-N53 by targeting the major resident cells in the wound tissue.