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Serine protease dipeptidyl peptidase IV (DPP-IV) (also referred to as CD26) is a type II membrane protein that modulates biological activities of peptide hormones, cytokines, and neuropeptides by removing two residues from the N termini of these peptides.Human DPP-IV shares 85% sequence identity with rat DPP-IV. Membrane-bound DPP-IV functions as a peptidase as well as binding partner for other proteins, such as adenosine deaminase and T-cell antigen (CD45) , and is involved in T-cell co-stimulation and tumor suppression. Soluble and membrane-bound forms of DPP-IV have similar catalytic activities. In vivo, DPP-IV proteins are heavily glycosylated and exist as homodimers, where each subunit is comprised of two structural domains: the α/β-hydrolase and β-propeller domains.The catalytic site is located in a large cavity formed between these two domains. Suppression of DPP-IV activity is an established strategy to treat type 2 diabetes mellitus.To date, E53a number of small molecule DPP-IV inhibitors have either become marketed products or are at different stages of clinical development.