Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H)--a novel potent and orally active immunosuppressive agent.
Patients with purine nucleoside phosphorylase (PNP) deficiency present a selective T-cell immunodeficiency. Inhibitors of PNP are, therefore, of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP from various species including human, mouse, rat, monkey and dog, with IC50 values ranging from 0.48 to 1.57 nM. BCX-1777, in the presence of 2'-deoxyguanosine (dGuo, 3-10 microM), inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction (MLR) and phytohemagglutinin (PHA) (IC50 values < 0.1-0.38 microM). BCX-1777 is a 10-100-fold more potent inhibitor of human lymphocyte proliferation than other known PNP inhibitors like PD141955 and BCX-34. Nucleotide analysis of human lymphocytes indicate that inhibition of proliferation by BCX-1777 correlates with dGTP levels in the cells. BCX-1777 has excellent oral bioavailability (63%) in mice. At a single dose of 10 mg/kg in mice, BCX-1777 elevates dGuo to approximately 5 microM. 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 human T-cells. However, in the human peripheral blood lymphocyte severe combined 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 dGuo 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 novel class of selective immunosuppressive agents that could have therapeutic utility in various T-cell disorders.
Bantia
S
S
Department of Biological Sciences, BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Suite B, Birmingham, AL 35244, USA. sbantia@biocryst.com
Miller
P J
PJ
Parker
C D
CD
Ananth
S L
SL
Horn
L L
LL
Kilpatrick
J M
JM
Morris
P E
PE
Hutchison
T L
TL
Montgomery
J A
JA
Sandhu
J S
JS
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006087:Graft vs Host Reaction / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113101:forodesine; D006160:Guanosine Triphosphate; D011683:Purine-Nucleoside Phosphorylase