{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:55:40Z","timestamp":1791269740498,"version":"4.1.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,4,10]]},"abstract":"<jats:p>\n                    Transition-state theory has led to the design of Immucillin-H\n (Imm-H), a picomolar inhibitor of purine nucleoside phosphorylase\n (PNP). In humans, PNP is the only route for degradation of\n deoxyguanosine, and genetic deficiency of this enzyme leads to\n profound T cell-mediated immunosuppression. This study reports the\n biological effects and mechanism of action of Imm-H on malignant T cell\n lines and on normal activated human peripheral T cells. Imm-H inhibits\n the growth of malignant T cell leukemia lines with the induction of\n apoptosis. Imm-H also inhibits activated normal human T cells\n after antigenic stimulation\n                    <jats:italic>in vitro<\/jats:italic>\n                    . However, Imm-H did\n not inhibit malignant B cells, colon cancer cell lines, or normal human\n nonstimulated T cells, demonstrating the selective activity of Imm-H.\n The effects on leukemia cells were mediated by the cellular\n phosphorylation of deoxyguanosine and the accumulation of dGTP, an\n inhibitor of ribonucleotide diphosphate reductase. Cells were protected\n from the toxic effects of Imm-H when deoxyguanosine was absent or\n when deoxycytidine was present. Guanosine incorporation into nucleic\n acids was selectively blocked by Imm-H with no effect on guanine,\n adenine, adenosine, or deoxycytidine incorporation. Imm-H may have\n clinical potential for treatment of human T cell leukemia and lymphoma\n and for other diseases characterized by abnormal activation of T\n lymphocytes. The design of Imm-H from an enzymatic transition-state\n analysis exemplifies a powerful approach for developing high-affinity\n enzyme inhibitors with pharmacologic activity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.071050798","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"4593-4598","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":177,"title":["Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes"],"prefix":"10.1073","volume":"98","author":[{"given":"Greg A.","family":"Kicska","sequence":"first","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Long","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"H\u00f6rig","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Fairchild","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Tyler","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H.","family":"Furneaux","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vern L.","family":"Schramm","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard L.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Microbiology and\r Immunology, and Surgery, Albert Einstein College of\r Medicine, Bronx, NY 10461; Carbohydrate Chemistry Team,\r Industrial Research Limited, Lower Hutt, New Zealand; and\r Bristol Myers\u2013Squibb, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,4,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197703242961203"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)40090-2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.24.11540"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.8.3.283"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.693"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi980658d"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar50049a002"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00211a033"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00004a008"},{"key":"e_1_3_3_10_2","volume-title":"Tetrahedron Lett.","author":"Horenstein B","year":"1993","unstructured":"B Horenstein, R F Zabinski, V L Schramm Tetrahedron Lett., 7213\u20137216. 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