Skip to main content
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Jul;39(7):1406–1413. doi: 10.1128/aac.39.7.1406

SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2-aminobenzylstatine moiety.

A Billich 1, G Fricker 1, I Müller 1, P Donatsch 1, P Ettmayer 1, H Gstach 1, P Lehr 1, P Peichl 1, D Scholz 1, B Rosenwirth 1
PMCID: PMC162753  PMID: 7492076

Abstract

A series of inhibitors of human immunodeficiency virus type 1 (HIV-1) proteinase containing the 2-aralkyl-amino-substituted statine moiety as a novel transition-state analog was synthesized, with the aim to obtain compounds which combine anti-HIV potency with oral bioavailability. The reduced-size 2-aminobenzylstatine derivative SDZ PRI 053, which contains 2-(S)-amino-3-(R)-hydroxyindane in place of an amino acid amide, is a potent and orally bioavailable inhibitor of HIV-1 replication. The antiviral activity of SDZ PRI 053 was demonstrated in various cell lines, in primary lymphocytes, and in primary monocytes, against laboratory strains as well as clinical HIV-1 isolates (50% effective dose = 0.028 to 0.15 microM). Cell proliferation was impaired only at 100- to 300-fold-higher concentrations. The mechanism of antiviral action of the proteinase inhibitor SDZ PRI 0.53 was demonstrated to be inhibition of gag precursor protein processing. The finding that the inhibitory potency of SDZ PRI 053 in chronic virus infection, determined by p24 release, was considerably lower than that in de novo infection may be explained by the fact that the virus particles produced in the presence of SDZ PRI 053 are about 50-fold less infectious than those from untreated cultures. Upon intravenous administration, half-lives in blood of 100 and 32 min in mice and rats, respectively, were measured. Oral bioavailability of SDZ PRI 053 in rodents was 20 to 60%, depending on the dose. In mice, rats, and dogs, the inhibitor levels after oral administration remained far above the concentrations needed to efficiently block HIV replication in vitro for a prolonged period. This compound is thus a promising candidate for clinical use in HIV disease.

Full Text

The Full Text of this article is available as a PDF (246.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alteri E., Bold G., Cozens R., Faessler A., Klimkait T., Lang M., Lazdins J., Poncioni B., Roesel J. L., Schneider P. CGP 53437, an orally bioavailable inhibitor of human immunodeficiency virus type 1 protease with potent antiviral activity. Antimicrob Agents Chemother. 1993 Oct;37(10):2087–2092. doi: 10.1128/aac.37.10.2087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bajkowski A. S., Frankfater A. Specific spectrophotometric assays for cathepsin B1. Anal Biochem. 1975 Sep;68(1):119–127. doi: 10.1016/0003-2697(75)90685-5. [DOI] [PubMed] [Google Scholar]
  3. Barrett A. J. Cathepsin G. Methods Enzymol. 1981;80(Pt 100):561–565. doi: 10.1016/s0076-6879(81)80044-4. [DOI] [PubMed] [Google Scholar]
  4. Barrett A. J. Leukocyte elastase. Methods Enzymol. 1981;80(Pt 100):581–588. doi: 10.1016/s0076-6879(81)80046-8. [DOI] [PubMed] [Google Scholar]
  5. Billich A., Charpiot B., Fricker G., Gstach H., Lehr P., Peichl P., Scholz D., Rosenwirth B. HIV proteinase inhibitors containing 2-aminobenzylstatine as a novel scissile bond replacement: biochemical and pharmacological characterization. Antiviral Res. 1994 Dec;25(3-4):215–233. doi: 10.1016/0166-3542(94)90005-1. [DOI] [PubMed] [Google Scholar]
  6. Billich A., Hammerschmid F., Winkler G. Purification, assay and kinetic features of HIV-1 proteinase. Biol Chem Hoppe Seyler. 1990 Mar;371(3):265–272. [PubMed] [Google Scholar]
  7. Böhlen P., Stein S., Dairman W., Udenfriend S. Fluorometric assay of proteins in the nanogram range. Arch Biochem Biophys. 1973 Mar;155(1):213–220. doi: 10.1016/s0003-9861(73)80023-2. [DOI] [PubMed] [Google Scholar]
  8. Cheng-Mayer C., Levy J. A. Distinct biological and serological properties of human immunodeficiency viruses from the brain. Ann Neurol. 1988;23 (Suppl):S58–S61. doi: 10.1002/ana.410230716. [DOI] [PubMed] [Google Scholar]
  9. Clavel F., Guyader M., Guétard D., Sallé M., Montagnier L., Alizon M. Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature. 1986 Dec 18;324(6098):691–695. doi: 10.1038/324691a0. [DOI] [PubMed] [Google Scholar]
  10. Darke P. L., Huff J. R. HIV protease as an inhibitor target for the treatment of AIDS. Adv Pharmacol. 1994;25:399–454. doi: 10.1016/s1054-3589(08)60438-x. [DOI] [PubMed] [Google Scholar]
  11. De Clercq E., Yamamoto N., Pauwels R., Balzarini J., Witvrouw M., De Vreese K., Debyser Z., Rosenwirth B., Peichl P., Datema R. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother. 1994 Apr;38(4):668–674. doi: 10.1128/aac.38.4.668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DelMar E. G., Largman C., Brodrick J. W., Geokas M. C. A sensitive new substrate for chymotrypsin. Anal Biochem. 1979 Nov 1;99(2):316–320. doi: 10.1016/s0003-2697(79)80013-5. [DOI] [PubMed] [Google Scholar]
  13. ERLANGER B. F., KOKOWSKY N., COHEN W. The preparation and properties of two new chromogenic substrates of trypsin. Arch Biochem Biophys. 1961 Nov;95:271–278. doi: 10.1016/0003-9861(61)90145-x. [DOI] [PubMed] [Google Scholar]
  14. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  15. Gazdar A. F., Carney D. N., Bunn P. A., Russell E. K., Jaffe E. S., Schechter G. P., Guccion J. G. Mitogen requirements for the in vitro propagation of cutaneous T-cell lymphomas. Blood. 1980 Mar;55(3):409–417. [PubMed] [Google Scholar]
  16. Greenlee W. J. Renin inhibitors. Med Res Rev. 1990 Apr-Jun;10(2):173–236. doi: 10.1002/med.2610100203. [DOI] [PubMed] [Google Scholar]
  17. Holzman T. F., Chung C. C., Edalji R., Egan D. A., Gubbins E. J., Rueter A., Howard G., Yang L. K., Pederson T. M., Krafft G. A. Recombinant human prorenin from CHO cells: expression and purification. J Protein Chem. 1990 Dec;9(6):663–672. doi: 10.1007/BF01024761. [DOI] [PubMed] [Google Scholar]
  18. Huff J. R. HIV protease: a novel chemotherapeutic target for AIDS. J Med Chem. 1991 Aug;34(8):2305–2314. doi: 10.1021/jm00112a001. [DOI] [PubMed] [Google Scholar]
  19. Ikeda K., Suzuki H., Okano T., Nakagawa S. Human spleen cathepsin D: its characterization and localization in human spleen. Int J Biochem. 1989;21(3):317–326. doi: 10.1016/0020-711x(89)90190-0. [DOI] [PubMed] [Google Scholar]
  20. Kageyama S., Anderson B. D., Hoesterey B. L., Hayashi H., Kiso Y., Flora K. P., Mitsuya H. Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins. Antimicrob Agents Chemother. 1994 May;38(5):1107–1111. doi: 10.1128/aac.38.5.1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kaplan A. H., Zack J. A., Knigge M., Paul D. A., Kempf D. J., Norbeck D. W., Swanstrom R. Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J Virol. 1993 Jul;67(7):4050–4055. doi: 10.1128/jvi.67.7.4050-4055.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kettner C., Mersinger L., Knabb R. The selective inhibition of thrombin by peptides of boroarginine. J Biol Chem. 1990 Oct 25;265(30):18289–18297. [PubMed] [Google Scholar]
  23. Kikukawa R., Koyanagi Y., Harada S., Kobayashi N., Hatanaka M., Yamamoto N. Differential susceptibility to the acquired immunodeficiency syndrome retrovirus in cloned cells of human leukemic T-cell line Molt-4. J Virol. 1986 Mar;57(3):1159–1162. doi: 10.1128/jvi.57.3.1159-1162.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kort J. J., Bilello J. A., Bauer G., Drusano G. L. Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother. 1993 Jan;37(1):115–119. doi: 10.1128/aac.37.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  26. Miyoshi I., Kubonishi I., Yoshimoto S., Akagi T., Ohtsuki Y., Shiraishi Y., Nagata K., Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981 Dec 24;294(5843):770–771. doi: 10.1038/294770a0. [DOI] [PubMed] [Google Scholar]
  27. Nagy K., Young M., Baboonian C., Merson J., Whittle P., Oroszlan S. Antiviral activity of human immunodeficiency virus type 1 protease inhibitors in a single cycle of infection: evidence for a role of protease in the early phase. J Virol. 1994 Feb;68(2):757–765. doi: 10.1128/jvi.68.2.757-765.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Otto M. J., Reid C. D., Garber S., Lam P. Y., Scarnati H., Bacheler L. T., Rayner M. M., Winslow D. L. In vitro anti-human immunodeficiency virus (HIV) activity of XM323, a novel HIV protease inhibitor. Antimicrob Agents Chemother. 1993 Dec;37(12):2606–2611. doi: 10.1128/aac.37.12.2606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pauwels R., Andries K., Desmyter J., Schols D., Kukla M. J., Breslin H. J., Raeymaeckers A., Van Gelder J., Woestenborghs R., Heykants J. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature. 1990 Feb 1;343(6257):470–474. doi: 10.1038/343470a0. [DOI] [PubMed] [Google Scholar]
  30. Pauwels R., Balzarini J., Baba M., Snoeck R., Schols D., Herdewijn P., Desmyter J., De Clercq E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods. 1988 Aug;20(4):309–321. doi: 10.1016/0166-0934(88)90134-6. [DOI] [PubMed] [Google Scholar]
  31. Perno C. F., Yarchoan R., Cooney D. A., Hartman N. R., Webb D. S., Hao Z., Mitsuya H., Johns D. G., Broder S. Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine. J Exp Med. 1989 Mar 1;169(3):933–951. doi: 10.1084/jem.169.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  33. Ralph P., Moore M. A., Nilsson K. Lysozyme synthesis by established human and murine histiocytic lymphoma cell lines. J Exp Med. 1976 Jun 1;143(6):1528–1533. doi: 10.1084/jem.143.6.1528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rey M. A., Krust B., Laurent A. G., Guétard D., Montagnier L., Hovanessian A. G. Characterization of an HIV-2-related virus with a smaller sized extracellular envelope glycoprotein. Virology. 1989 Nov;173(1):258–267. doi: 10.1016/0042-6822(89)90242-0. [DOI] [PubMed] [Google Scholar]
  35. Richards A. D., Phylip L. H., Farmerie W. G., Scarborough P. E., Alvarez A., Dunn B. M., Hirel P. H., Konvalinka J., Strop P., Pavlickova L. Sensitive, soluble chromogenic substrates for HIV-1 proteinase. J Biol Chem. 1990 May 15;265(14):7733–7736. [PubMed] [Google Scholar]
  36. Robins T., Plattner J. HIV protease inhibitors: their anti-HIV activity and potential role in treatment. J Acquir Immune Defic Syndr. 1993 Feb;6(2):162–170. [PubMed] [Google Scholar]
  37. Rosenwirth B., Billich A., Datema R., Donatsch P., Hammerschmid F., Harrison R., Hiestand P., Jaksche H., Mayer P., Peichl P. Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog. Antimicrob Agents Chemother. 1994 Aug;38(8):1763–1772. doi: 10.1128/aac.38.8.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Scholz D., Billich A., Charpiot B., Ettmayer P., Lehr P., Rosenwirth B., Schreiner E., Gstach H. Inhibitors of HIV-1 proteinase containing 2-heterosubstituted 4-amino-3-hydroxy-5-phenylpentanoic acid: synthesis, enzyme inhibition, and antiviral activity. J Med Chem. 1994 Sep 16;37(19):3079–3089. doi: 10.1021/jm00045a013. [DOI] [PubMed] [Google Scholar]
  39. Thompson W. J., Fitzgerald P. M., Holloway M. K., Emini E. A., Darke P. L., McKeever B. M., Schleif W. A., Quintero J. C., Zugay J. A., Tucker T. J. Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design. J Med Chem. 1992 May 15;35(10):1685–1701. doi: 10.1021/jm00088a003. [DOI] [PubMed] [Google Scholar]
  40. Vacca J. P., Dorsey B. D., Schleif W. A., Levin R. B., McDaniel S. L., Darke P. L., Zugay J., Quintero J. C., Blahy O. M., Roth E. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4096–4100. doi: 10.1073/pnas.91.9.4096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vella S. HIV therapy advances. Update on a proteinase inhibitor. AIDS. 1994 Sep;8 (Suppl 3):S25–S29. doi: 10.1097/00002030-199409001-00006. [DOI] [PubMed] [Google Scholar]
  42. Wachsmuth E. D., Fritze I., Pfleiderer G. An aminopeptidase occurring in pig kidney. I. An improved method of preparation. Physical and enzymic properties. Biochemistry. 1966 Jan;5(1):169–174. doi: 10.1021/bi00865a022. [DOI] [PubMed] [Google Scholar]
  43. Weiss A., Wiskocil R. L., Stobo J. D. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984 Jul;133(1):123–128. [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES