Abstract
CD26, a membrane-bound ectopeptidase, is known as an activated T cell marker with dipeptidyl peptidase IV (DPPIV) activity that has diverse functional roles in the regulation of peptide hormones, neuropeptides, chemokines and growth factors. We recently isolated a novel inhibitor of DPPIV, sulphostin, from culture broth of Streptomyces sp. MK251-43F3. We investigated herein the hematopoietic effect of sulphostin in mice and found that sulphostin induced the production of granulocyte colony-stimulating factor (G-CSF), stimulated myeloblasts in bone marrow, and increased neutrophil numbers in peripheral blood in both normal mice and mice with cyclophosphamide-induced leucopenia. Sulphostin desulfonate, in addition to sulphostin, has a similar inhibitory effect on DPPIV and stimulatory effect on neutrophils. These results suggest that DPPIV/CD26 might be a novel target for hematopoietic stimulation and DPPIV inhibitors including sulphostin and derivatives may be candidates for further development.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Meester ID, Korom S, Damme JV, Scharpe S . CD26, let it cut or cut it down. Immunol Today 20: 367–375 ( 1999)
Augustyns K, Bal G, Thonus G, Belyaev A, Zhang XM, Bollaert W, Lambeir AM, Durinx C, Goosens F, Haemers A . The unique properties of dipeptidyl-peptidase IV (DPPIV) and the therapeutic potential of DPPIV inhibitors. Current Medical Chem. 6: 311–327 ( 1999)
Christopherson K, Hangoc WG, Mantel CR, Broxmeyer HE . Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 305: 1000–1003 ( 2004)
Cheng JD, Dunbrack RL, Valianou JM, Rogatko A, Alpaugh K, Weiner LM . Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res 62: 67–72 ( 2002)
Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, Mangold BL, Russell ME, Hughes TE . 1-[[(3-Hydroxy-1-adamantyl)amino] acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 46: 2774–2789 ( 2003)
Akiyama T, Abe M, Harada S, Kojima F, Sawa R, Takahashi Y, Naganawa H, Homma Y, Hamada M, Yamaguchi A, Aoyagi T, Muraoka Y, Takeuchi T . Sulphostin, a potent inhibitor for dipeptidyl peptidase IV from Streptomyces sp. MK251-43F3. J Antibiot 54: 744–746 ( 2001)
Abe M, Akiyama T, Nakamura H, Kojima F, Harada S, Muraoka Y . First synthesis and determination of the absolute configuration of sulphostin, a novel inhibitor of dipeptidyl peptidase IV. J Nat Prod 67: 999–1004 ( 2004)
Abe M, Akiyama T, Umezawa Y, Yamamoto K, Nagai M, Yamazaki H, Ichikawa Y, Muraoka Y . Synthesis and biological activity of sulphostin analogues, novel dipeptidyl peptidase IV Inhibitors. Bioorg Med Chem 13: 785–797 ( 2005)
Coutts SJ, Kelly TA, Snow RJ, Kenedy CA, Barton RW, Adams J, Krolikowski DA, Freeman DM, Cambell SJ, Ksiazek IF, Bachovchin WW . Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides. J Med Chem 39: 2087 ( 1996)
Darmoul D, Lacasa M, Baricault L, Marguet D, Sapin C, Trotot P, Barbat A, Trugnan G . Dipeptidyl peptidase IV (CD26) gene expression in enterocyte-like colon cancer cell lines HT-29 and Caco-2. Cloning of the complete human coding sequence and changes of dipeptidyl peptidase IV mRNA levels during cell differentiation. J Biol Chem 267: 4824–4833 ( 1992)
Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, Huber R, Bode W, Demuth HU, Brandstetter H . The crystal structure dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc. Natl. Acad. Sci. USA 100: 5063–5068 ( 2003)
Conarello SL, Li Z, Ronan J, Roy RS, Zhu L, Jiang G, Liu F, Woods J, Zycband E, Moller DE, Thornberry NA, Zhang BB . Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 100: 6825–6830 ( 2003)
Rosenblum J, Kozarich JW . Prolyl peptidase: a serine protease subfamily with high potential for drug discovery. Current Opinion in Chemical Biology 7: 496–504 ( 2003)
Umezawa H, Aoyagi T, Ogawa K, Naganawa H, Hamada M, Takeuchi T . Diprotin A and B, inhibitor of dipeptidyl peptidase IV, produced by bacteria. J Antibiot 37: 422–425 ( 1984)
Reinhold D, Hemmer B, Gran B, Steinbrecher A, Brocke S, Kahne T, Wrenger S, Born I, Faust J, Neubert K, Martin R, Ansorge S . Dipeptidyl peptidase IV (CD26): role in T cell activation and autoimmune disease. Adv Exp Med Biol 477: 155–160 ( 2000)
Ahren B, Landin-Olsson M, Jansson PA, Sevensson M, Holmes D, Schweizer A . Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagons levels in type 2 diabetes. J Clin Endocrinol Metab 89: 2078–2084 ( 2004)
Guan E, Wang J, Norcross MA . Amino-terminal processing of MIP-1 beta/CCL4 by CD26/dipeptidylpeptidase IV. J Cell Biochem 92: 53–64 ( 2004)
Christopherson KW 2nd, Hangoc G, Broxmeyer HE . Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1α-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 169: 7000–7008 ( 2002)
Broxmeyer HE, Kohli L, Kim CH, Lee Y, Mantel C, Cooper S, Hangoc G, Shaheen M, Li X, Clapp DW . Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(α)i proteins and enhances engraftment of competitive, repopulating stem cells. J Leukoc Biol 73, 630–638 ( 2003)
Bristol LA, Bachovchin W, Laszlo T . Inhibition of CD26 enzyme activity with Pro-boropro stimulates rat granulocyte/macrophage colony formation and thymocyte proliferation in vitro. Blood 85: 3602–3609 ( 1995)
Adams S, Miller GT, Jesson MI, Watanabe T, Jones B, Waller BP . PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res 64: 5471–5480 ( 2004)
Jones B, Adams S, Miller GT, Jesson MI, Watanabe T, Waller BP . Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies. Blood 102: 1641–1648 ( 2003)
Scanlan MJ, Raj BKM, Calvo B, Garin-chesa P, Sanz-moncasi MP, Healey JH, Old LJ, Rettig WJ . Molecular cloning of fibroblast activation protein α, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA 91: 5657–5661 ( 1994)
Park JE, Lendr MC, Zimmermann RN, Garin-ches P, Old LJ, Rettig WJ . Fibroblast activation protein, a dual specificity serine protease expressed in relative human tumor stromal fibroblasts. J Biol Chem 274: 36505–36512 ( 1999)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abe, M., Abe, F., Nishimura, C. et al. Sulphostin, a Novel Inhibitor of Dipeptidyl Peptidases IV (DPPIV) That Stimulates Hematopoiesis in Mice. J Antibiot 58, 111–117 (2005). https://doi.org/10.1038/ja.2005.14
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1038/ja.2005.14
