Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies.
In hematopoiesis, cytokine levels modulate blood cell replacement, self-renewal of stem cells, and responses to disease. Feedback pathways regulating cytokine levels and targets for therapeutic intervention remain to be determined. Amino boronic dipeptides are orally bioavailable inhibitors of dipeptidyl peptidases. Here we show that the high-affinity inhibitor Val-boro-Pro (PT-100) can stimulate the growth of hematopoietic progenitor cells in vivo and can accelerate neutrophil and erythrocyte regeneration in mouse models of neutropenia and acute anemia. Hematopoietic stimulation by PT-100 correlated with increased cytokine levels in vivo. In vitro, PT-100 promoted the growth of primitive hematopoietic progenitor cells by increasing granulocyte-colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and IL-11 production by bone marrow stromal cells. Two molecular targets of PT-100 are expressed by stromal cells- CD26/DPP-IV and the closely related fibroblast activation protein (FAP). Because PT-100 was active in the absence of CD26, FAP appears to be the hematopoietic target for PT-100. Interaction of PT-100 with the catalytic site seems to be required because amino-terminal acetylation of PT-100 abrogated enzyme inhibition and hematopoietic stimulation. PT-100 is a therapeutic candidate for the treatment of neutropenia and anemia. The data support increasing evidence that dipeptidyl peptidases can regulate complex biologic systems by the proteolysis of signaling peptides.
Jones
Barry
B
Point Therapeutics Inc, 75 Kneeland St, Boston, MA 02111, USA. bjones@pther.com
Adams
Sharlene
S
Miller
Glenn T
GT
Jesson
Michael I
MI
Watanabe
Takeshi
T
Wallner
Barbara P
BP
D000740:Anemia / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology; D001897:Boronic Acids / Q000494:pharmacology*; D018938:Caco-2 Cells; D019070:Cell Lineage; D003520:Cyclophosphamide / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000166:cytology / Q000201:enzymology; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009503:Neutropenia / Q000188:drug therapy* / Q000503:physiopathology; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology / Q000201:enzymology
D001897:Boronic Acids; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C477478:PT-100 dipeptide; D003520:Cyclophosphamide; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4