Purine nucleoside phosphorylase inhibitor BCX-1777 (immucillin-H) - a novel potent and orally active immunosuppressive agent

Citation
S. Bantia et al., Purine nucleoside phosphorylase inhibitor BCX-1777 (immucillin-H) - a novel potent and orally active immunosuppressive agent, INT IMMUNO, 1(6), 2001, pp. 1199-1210
Citations number
33
Categorie Soggetti
Immunology
Journal title
INTERNATIONAL IMMUNOPHARMACOLOGY
ISSN journal
15675769 → ACNP
Volume
1
Issue
6
Year of publication
2001
Pages
1199 - 1210
Database
ISI
SICI code
1567-5769(200106)1:6<1199:PNPIB(>2.0.ZU;2-0
Abstract
Patients with purine nucleoside phosphorylase (PNP) deficiency present a se lective T-cell immunodeficiency. Inhibitors of PNP are, therefore, of inter est as potential T-cell selective immunosuppressive agents. BCX-1777 is a p otent inhibitor of PNP from various species including human, mouse, rat, mo nkey and dog, with IC50 values ranging from 0.48 to 1.57 nM. BCX-1777, in t he presence of 2 ' -deoxyguanosine (dGuo, 3-10 muM), inhibits human lymphoc yte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction (MLR) and phytohemagglutinin (PHA) (IC50 values < 0.1-0.38 muM) BCX-1777 is a 10-100-fold more potent inhibitor of human ly mphocyte proliferation than other known PNP inhibitors like PD141955 and BC X-34. Nucleotide analysis of human lymphocytes indicate that inhibition of proliferation by BCX-1777 correlates with dGTP levels in the cells. BCX-177 7 has excellent oral bioavailability (63%) in mice. At a single dose of 10 mg/kg in mice, BCX-1777 elevates dGuo to approximately 5 muM. BCX-1777 was not effective in mouse T-cell models such as delayed type hypersensitivity (DTH) and splenomegaly because mouse T-cells do not accumulate dGTP as do h uman T-cells. However, in the human peripheral blood lymphocyte severe comb ined immunodeficiency (hu-PBL-SCID) mouse model, BCX-1777 was effective in prolonging the life span 2-fold or more. This is the first known example of a PNP inhibitor that elevates dCuo in mice similar to the levels observed in PNP-deficient patients. Furthermore, these dGuo levels are also required for in vitro T-cell inhibition by BCX-1777. Thus, BCX-1777 represents a no vel class of selective immunosuppressive agents that could have therapeutic utility in various T-cell disorders. (C) 2001 Elsevier Science B.V. All ri ghts reserved.