Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1-directed novel therapeutics

Vascular cell adhesion molecule-1 (VCAM-1) has been well established as a critical contributor to atherosclerosis and consequently as an attractive therapeutic target for anti-atherosclerotic drug candidates. Many publications have demonstrated that disrupting the VCAM-1 function blocks monocyte infiltration into the sub-endothelial space, which effectively prevents macrophage maturation and foam cell transformation necessary for atherosclerotic lesion formation. Currently, most VCAM-1-inhibiting drug candidates in pre-clinical and clinical testing do not directly target VCAM-1 itself but rather down-regulate its expression by inhibiting upstream cytokines and transcriptional regulators. However, the pleiotropic nature of these regulators within innate immunity means that optimizing dosage to a level that suppresses pathological activity while preserving normal physiological function is extremely challenging and oftentimes infeasible. In recent years, highly specific pharmacological strategies that selectively inhibit VCAM-1 function have emerged, particularly peptide- and antibody-based novel therapeutics. Studies in such VCAM-1-directed therapies so far remain scarce and are limited by the constraints of current experimental atherosclerosis models in accurately representing the complex pathophysiology of the disease. This has prompted the need for a comprehensive review that recounts the evolution of VCAM-1-directed pharmaceuticals and addresses the current challenges in novel anti-atherosclerotic drug development. Graphical abstract

Automated summary

Vascular cell adhesion molecule-1 (VCAM-1) plays a crucial role in atherosclerosis and has been targeted for anti-atherosclerotic drug development. Most current VCAM-1-inhibiting drug candidates indirectly down-regulate VCAM-1 expression by inhibiting upstream cytokines, but optimizing dosage to balance pathological activity and normal physiological function is challenging. Recently, specific strategies that selectively inhibit VCAM-1 function, such as peptide- and antibody-based therapeutics, have emerged. However, studies on these novel VCAM-1-directed therapies are limited by the complexity of atherosclerosis pathophysiology.