title: Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome.
abstract: Obesity-induced insulin resistance and metabolic syndrome continue to pose an important public health challenge worldwide as they significantly increase the risk of type 2 diabetes and atherosclerotic cardiovascular disease. Advances in the pathophysiologic understanding of this process has identified that chronic inflammation plays a pivotal role. In this regard, given that both animal models and human studies have demonstrated that the interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin is not only critical for normal immune response but also is upregulated in the setting of metabolic syndrome, PSGL-1/P-selectin interactions provide a novel target for preventing and treating resultant disease. Current approaches of interfering with PSGL-1/P-selectin interactions include targeted antibodies, recombinant immunoglobulins that competitively bind P-selectin, and synthetic molecular therapies. Experimental models as well as clinical trials assessing the role of these modalities in a variety of diseases have continued to contribute to the understanding of PSGL-1/P-selectin interactions and have demonstrated the difficulty in creating clinically relevant therapeutics. Most recently, however, computational simulations have further enhanced our understanding of the structural features of PSGL-1 and related glycomimetics, which are responsible for high-affinity selectin interactions. Leveraging these insights for the design of next generation agents has thus led to development of a promising synthetic method for generating PSGL-1 glycosulfopeptide mimetics for the treatment of metabolic syndrome.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Mass; Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass.
authors.forename: Madhukar S
authors.initials: MS
authors.lastname: Patel
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass.
authors.forename: David
authors.initials: D
authors.lastname: Miranda-Nieves
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass.
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Haller
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass. Electronic address: echaikof@bidmc.harvard.edu.
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Chaikof
mesh_terms: D015195:Drug Design; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D024821:Metabolic Syndrome / Q000188:drug therapy*; D019007:P-Selectin / Q000494:pharmacology*
chemical_list: D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein