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The clinical compound screening initiative A challenge to the

By Christine Turner,2014-06-18 01:01
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The clinical compound screening initiative A challenge to the

SUPPLEMENTARY TABLE 1: Examples of existing drugs used to treat new diseases

    Drug Original disease New disease Amphotericin Antifungal Leishmaniasis

    Interferes with fungal membranes

    by binding to cell membrane

    sterols 11Arsenic “Oldest drug in the world Acute promyelocytic leukemia thUsed in early 20 century to treat Degrades PML-RAR fusion protein

    tuberculosis and syphilis 2Ceftriaxone Antibiotic Amyotrophic Lateral Sclerosis

    Increases glutamate transporter expression ?-lactam inhibits bacterial cell

    wall synthesis 3Dapsone Leprosy Malaria

    Inhibits folic acid synthesis Combined with chloroproguanil in LapDap; 4approved by UK for treatment of malaria 5DB289 Pneumocystis Malaria and early stage African 5 Trypanosomiasis . Eflornithine Cancer African trypanosomes

    Suicide inhibitor of ornithine Inhibits protozoan ornithine decarboxylase

    decarboxylase, blocking polyamine but is specific for African trypanosomes due 6biosynthesis. Failed in clinical to low blood polyamine levels . 6trials Established treatment. .

    Fosmidomycin Urinary tract infections Antimalarial 7Inhibits isoprenoid synthesis . Nonmevalonate pathway of isoprenoid

    biosynthesis identified in P. falciparum 3using genomic techniques . Currently in

    clinical trials alone and in combination 8,9with clindamycin. Fumagillin Antiamebic Anti-cancer angiogenesis inhibitor

    Unknown mechanism. Blocks endothelial cell growth by inhibiting 10type II methionine aminopeptidase . TNP- 470, a fumagillin analog, is currently in Phase III clinical trials for brain, breast, 11cervical and prostate cancer . Miltefosine Cancer Visceral leishmania

    May induce apoptosis by inhibiting Unknown mechanism. Registered for use in 1213lipid biosynthesis India in 2002 . . Minocycline Antibiotic Amyotrophic lateral sclerosis

    Blocks entry of the aminoacyl Inhibits cytochrome C release from

    tRNA into the ribosome.mitochondria. Delays disease onset and 1extends survival of ALS mice . Non-steroidal anti-Anti-inflammatory Alzheimer’s disease

    Cyclooxygenase inhibitor Reduce brain Aβ levels and amyloid plaque inflammatory 14burden 1512Paromomycin Amebicide Visceral leishmaniasis

    Oligosaccharide antibiotic Administered by injection Pentamidine Pneumocystis carinii Early stage trypanosome infection

    pneumonia and antimony resistant leishmaniasis 16

    Quinacrine Antimalarial Prion diseases 18Interferes with heme crystallization Potently inhibits prion formation .

    17 Anecdotal reports of improvement in 19patients with Creutzfeldt-Jakob disease . Retinoic acid Acne Acute promyelocytic leukemia

    Activates transcription of genes involved in 20differentiation Serotonin receptor Antipsychotic Progressive multifocal antagonists leukoencephalopathy

    Inhibit human polyomavirus (JCV) infection 21of glial cells 22Thalidomide Sedative Cancer

    Potent teratogen Inhibits angiogenesis

REFERENCES:

1. Zhu, S. et al. Minocycline inhibits cytochrome c release and delays progression of

    amyotrophic lateral sclerosis in mice. Nature 417, 74-8 (2002).

    2. Rothstein, J. D. et al. Beta-lactam antibiotics offer neuroprotection by increasing

    glutamate transporter expression. Nature 433, 73-7 (2005).

    3. Jomaa, H. et al. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as

    antimalarial drugs. Science 285, 1573-6 (1999).

    4. Lang, T. & Greenwood, B. The development of Lapdap, an affordable new treatment for

    malaria. Lancet Infect Dis 3, 162-8 (2003).

    5. Yeates, C. DB-289 Immtech International. IDrugs 6, 1086-93 (2003). 6. Marton, L. J. & Pegg, A. E. Polyamines as targets for therapeutic intervention. Annu Rev

    Pharmacol Toxicol 35, 55-91 (1995).

    7. Shigi, Y. Inhibition of bacterial isoprenoid synthesis by fosmidomycin, a phosphonic

    acid-containing antibiotic. J Antimicrob Chemother 24, 131-45 (1989). 8. Missinou, M. A. et al. Fosmidomycin for malaria. Lancet 360, 1941-2 (2002). 9. Borrmann, S. et al. Fosmidomycin-clindamycin for Plasmodium falciparum Infections in

    African children. J Infect Dis 189, 901-8 (2004).

    10. Griffith, E. C. et al. Methionine aminopeptidase (type 2) is the common target for

    angiogenesis inhibitors AGM-1470 and ovalicin. Chem Biol 4, 461-71 (1997). 11. Kruger, E. A., and Figg, W.D. TNP-470: an angiogenesis inhibitor in clinical

    development for cancer. Expert Opin Investig Drugs 9, 1383-96 (2000). 12. Fidock, D. A., Rosenthal, P. J., Croft, S. L., Brun, R. & Nwaka, S. Antimalarial drug

    discovery: efficacy models for compound screening. Nat Rev Drug Discov 3, 509-20

    (2004).

    13. Sundar, S. et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347,

    1739-46 (2002).

    14. Guerin, P. J. et al. Malaria: current status of control, diagnosis, treatment, and a proposed

    agenda for research and development. Lancet Infect Dis 2, 564-73 (2002). 15. Botero, D. Chemotherapy of human intestinal parasitic diseases. Annu Rev Pharmacol

    Toxicol 18, 1-15 (1978).

    16. Docampo, R. & Moreno, S. N. Current chemotherapy of human African trypanosomiasis.

    Parasitol Res 90 Supp 1, S10-3 (2003).

17. Chong, C. R. & Sullivan, D. J., Jr. Inhibition of heme crystal growth by antimalarials and

    other compounds: implications for drug discovery. Biochem Pharmacol 66, 2201-12

    (2003).

    18. Korth, C., May, B. C., Cohen, F. E. & Prusiner, S. B. Acridine and phenothiazine

    derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A 98,

    9836-41 (2001).

    19. Nakajima, M. et al. Results of quinacrine administration to patients with Creutzfeldt-

    Jakob disease. Dement Geriatr Cogn Disord 17, 158-63 (2004).

    20. Fang, J. et al. Treatment of acute promyelocytic leukemia with ATRA and As2O3: a

    model of molecular target-based cancer therapy. Cancer Biol Ther 1, 614-20 (2002). 21. Elphick, G. F. et al. The human polyomavirus, JCV, uses serotonin receptors to infect

    cells. Science 306, 1380-3 (2004).

    22. D'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of

    angiogenesis. Proc Natl Acad Sci U S A 91, 4082-5 (1994).

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