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The Road to Fortovase. A History of Saquinavir, the First Human Immunodeficiency Virus Protease Inhibitor

  • Chapter
Proteases as Targets for Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 140))

Abstract

Since the early 1980s, acquired immunodeficiency syndrome (AIDS) has evolved from a seemingly rare disease, first seen in small numbers of individuals in urban areas of the United States, into a worldwide epidemic. The syndrome is characterised by severe impairment of the immune system, resulting in infection by “opportunistic” pathogens and, ultimately, death. A recent joint report by the United Nations Programme on HIV/AIDS and the World Health Organization estimates that over 30 million people (one in every 100 sexually active adults worldwide) are living with human immunodeficiency virus (HIV) or AIDS. If the current transmission rate of around 16,000 new infections every day is not reduced, this number is predicted to exceed 40 million by the year 2000.

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References

  • Aboulker JP, Swart AM (1993) Preliminary analysis of the Concorde trial. Lancet 341:889–890

    Article  PubMed  CAS  Google Scholar 

  • Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868–871

    Article  PubMed  Google Scholar 

  • Borleffs JC on behalf of the CHEESE Study Team (1998) First comparative study of saquinavir soft-gel capsules vs indinavir as part of triple therapy regimen (CHEESE) (abstract). Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago 1–5 Feb 1998, no.387b

    Google Scholar 

  • Boucher C (1996) Rational approaches to resistance: using saquinavir. AIDS 10[Suppl 1]:S15–S19

    PubMed  CAS  Google Scholar 

  • Broadhurst AV, Roberts NA, Ritchie AJ, Handa BK, Kay C (1991) Assay of HIV-1 pro-teinase: a colorimetric method using small peptide substrates. Anal Biochem 193: 280–286

    Article  PubMed  CAS  Google Scholar 

  • Carr A, Marriott D, Field A, Vasak E, Cooper DA (1998) Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 351:256–261

    Article  PubMed  CAS  Google Scholar 

  • Chun T-W, Stuyver L, Mizell SB, Ehler LA, Mican JAM, Baseler M, Lloyd AL, Nowak MA, Fauci AS (1997) Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 94:13193–13197

    Article  PubMed  CAS  Google Scholar 

  • Clavel F, Guyader M, Guetard D, Salle M, Montagnier L, Alizon M (1986) Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature 324:691–695

    Article  PubMed  CAS  Google Scholar 

  • Connell EV, Hsu M-C, Richman DD (1994) Combinative interactions of a human immunodeficiency virus (HIV) tat antagonist with HIV reverse transcriptase inhibitors and an HIV proteinase inhibitor. Antimicrob Agents Chemother 38: 348–352

    Article  PubMed  CAS  Google Scholar 

  • Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS (1991a) Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res 16:295–305

    Article  PubMed  CAS  Google Scholar 

  • Craig JC, Grief C, Mills JS, Hockley D, Duncan IB, Roberts NA (1991b) Effects of a specific inhibitor of HIV proteinase (Ro 31-8959) on virus maturation in a chronically infected promonocytic cell line (U1). Antiviral Chem Chemother 2:181–186

    CAS  Google Scholar 

  • Craig JC, Duncan IB, Whittaker LN, Roberts NA (1993a) Antiviral synergy between inhibitors of HIV proteinase and reverse transcriptase. Antiviral Chem Chemother 4:161–166

    CAS  Google Scholar 

  • Craig JC, Whittaker L, Duncan IB, Roberts NA (1993b) In vitro resistance to an inhibitor of HIV proteinase (Ro 31-8959) relative to inhibitors of reverse transcriptase (AZT and TIBO). Antiviral Chem Chemother 4:335–339

    CAS  Google Scholar 

  • Craig JC, Whittaker LN, Duncan IB, Roberts NA (1994) In vitro anti-HIV and cytotoxicological evaluation of the triple combination: AZT and ddC with HIV proteinase inhibitor saquinavir (Ro 31–8959). Antiviral Chem Chemother 5:380–386

    CAS  Google Scholar 

  • Craig C, O’Sullivan E, Cammack N (1998) Increased exposure to the HIV protease inhibitor saquinavir (SQV) does not alter the nature of key resistance mutations (abstract). Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago 1–5 Feb 1998, no. 398

    Google Scholar 

  • Eagling VA, Back DJ, Barry MG (1997) Differential inhibition of cytochrome P450 isoforms by the protease inhibitors ritonavir, saquinavir and indinavir. Br J Pharmacol 44:190–194

    CAS  Google Scholar 

  • Egger M, Hirschel B, Francioli P, Sudre P, Wirz M, Flepp M, Rickenbach M, Malinverni R, Vernazza P, Battegay M (1997) Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV Cohort Study. BMJ 315:1194–1199

    Article  PubMed  CAS  Google Scholar 

  • Ermolieff J, Lin X, Tang J (1997) Kinetic properties of saquinavir-resistant mutants of human immunodeficiency type 1 protease and their implications in drug resistance in vivo. Biochemistry 36:12364–12370

    Article  PubMed  CAS  Google Scholar 

  • Farrar G, Mitchell AM, Hooper H, Stewart F, Malcolm SL (1994) Prediction of potential drug interactions of saquinavir (Ro 31–8959) from in vitro data. Br J Clin Pharmacol 38:162P

    Google Scholar 

  • Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278:1295–1300

    Article  PubMed  CAS  Google Scholar 

  • Fitzsimmons ME, Collins JM (1997) Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P450 3A4. Potential contribution to high first-pass metabolism. Drug Metab Dispos 25:256–266

    PubMed  CAS  Google Scholar 

  • Galpin S, Roberts NA, O’Connor T, Jeffries DJ, Kinchington D (1994) Antiviral properties of the HIV-1 proteinase inhibitor Ro 31-8959. Antiviral Chem Chemother 5:43–45

    CAS  Google Scholar 

  • Gazzard BG, Moyle GJ, Weber J, Johnson M, Bingham JS, Brettle R, Churchill D, Fisher M, Griffin G, Jefferies D, King E, Gormer R, Lee C, Pozniak A, Smith JR, Tudor-Williams G, Williams I (1997) British HIV Association guidelines for antiretroviral therapy of HIV seropositive individuals. Lancet 349:1086–1092

    Article  Google Scholar 

  • Graves MC, Lim JJ, Heimer EP, Kramer R (1988) An 11-KD form of human immu-nodeficiency virus protease expressed in Escherichia coli is sufficient for enzymatic activity. Proc Natl Acad Sci USA 85:2449–2453

    Article  PubMed  CAS  Google Scholar 

  • Hall MJ, Duncan IB (1988) Antiviral drug and interferon combinations. In: Field HJ (ed) Antiviral agents: the development and assessment of antiviral chemotherapy. CRC, Boca Raton, 2:29–84

    Google Scholar 

  • Haubrich R, Lalezari J, Follansbee SE, Gill M J, Hirsch M, Richman D, Mildvan D, Burger HU, Beattie D, Donatacci L, Salgo MP (1998) Improved survival and reduced clinical progression in HIV-infected patients with advanced disease treated with saquinavir plus zalcitabine. Antiviral Ther 3:33–42

    CAS  Google Scholar 

  • Holmes IN, Mahmood N, Karpas A, Petrik J, Kinchington D, O’Connor T, Jeffries DJ, Desmyter J, De Clercq E, Pauwels R, Hay A (1991) Screening of compounds for activity against HIV: a collaborative study. Antiviral Chem Chemother 2:287–293

    CAS  Google Scholar 

  • ves KJ, Jacobsen H, Galpin SA, Garaev MM, Dorrell L, Mous J, Bragman K, Weber JN (1997) Emergence of resistant variants of HIV in vivo during monotherapy with the protease inhibitor saquinavir. J Antimicrob Chemother 39:771–779

    Article  Google Scholar 

  • Jacobsen H, Ahlborn-Laake L, Gugel R, Mous J (1992) Progression of early steps of human immunodeficiency virus type 1 replication in the presence of an inhibitor of viral protease. J Virol 66:5087–5091

    PubMed  CAS  Google Scholar 

  • Jacobsen H, Yasargil K, Winslow DL, Craig JC, Krohn A, Duncan IB, Mous J (1995) Characterisation of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology 206:527–534

    Article  PubMed  CAS  Google Scholar 

  • Jacobsen H, Hanggi M, Ott M, Duncan IB, Owen S, Andreoni M, Vella S, Mous Jan (1996) In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies. J Infect Dis 173:1379–1387

    Article  PubMed  CAS  Google Scholar 

  • Johnson VA, Merrill DP, Chou T-C, Hirsch MS (1992) Human immunodeficiency virus type-1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2,3-dideoxycytidine or recombinant interferon αA against zidovudine-sensitive or-resistant HIV-1 in vitro. J Infect Dis 166:1143–1146

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann D, Pantaleo G, Sudre P, Telenti A (1998) CD4+T-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretoviral therapy (HAART). Swiss HIV Cohort Study. Lancet 351:723–724

    Article  PubMed  CAS  Google Scholar 

  • Kitchen VS, Skinner C, Ariyoshi K, Lane EA, Duncan IB, Burckhardt J, Burger HU, Bragman K, Pinching AJ, Weber JN (1995) Safety and activity of saquinavir in HIV infection. Lancet 345:952–955

    Article  PubMed  CAS  Google Scholar 

  • Kohl NE, Emini EA, Schlief WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM, Sigal IS (1988) Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci USA 85:4686–4690

    Article  PubMed  CAS  Google Scholar 

  • Kramer RA, Schaber MD, Skalka AM, Ganguly K, Wong-Staal F, Reddy EP (1986) HTLV-III gag-protein is processed in yeast cells by the virus pol-protease. Science 231:1580–1584

    Article  PubMed  CAS  Google Scholar 

  • Larder BA, Darby G, Richman DD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731–1734

    Article  PubMed  CAS  Google Scholar 

  • Le Grice SFJ, Mills J, Mous J (1988) Active site mutagenesis of the AIDS virus protease and its alleviation by trans complementation. EMBO J 7:2547–2553

    PubMed  Google Scholar 

  • Lightfoote MM, Coligan JE, Folks TM, Fauci AS, Martin MA, Venkatesan S (1986) Structural characterization of reverse transcriptase and endonuclease polypeptides of the acquired immunodeficiency syndrome retrovirus. J Virol 60:771–775

    PubMed  CAS  Google Scholar 

  • Lillehoj EP, Salazar FHR, Mervis RJ, Raum MG, Chan HW, Ahmad N, Venkatesan S (1988) Purification and structural characterization of the putative gag-pol protease of human immunodeficiency virus. J Virol 62:3053–3058

    PubMed  CAS  Google Scholar 

  • Martin JA, Mobberley MA, Redshaw S, Burke A, Tyms AS, Ryder TA (1991) The inhibitory activity of a peptide derivative against the growth of simian immunodeficiency virus in C8166 cells. Biochem Biophys Res Comm 176:180

    Article  PubMed  CAS  Google Scholar 

  • Mellors JW, Larder BA, Schinazi RF (1995) Mutations in HIV-1 reverse transcriptase and protease associated with drug resistance. Int Antiviral News 3:8–13

    Google Scholar 

  • Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tija JF, Gibbons SE, Breckenridge AM, Back DJ (1997) Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS (London) 11:F29–F33

    Article  CAS  Google Scholar 

  • Merry C, Barry MG, Mulcahy FM, Back DJ (1998) Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV infected patients (abstract). Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago 1-5 Feb 1998, no. 352

    Google Scholar 

  • Mitsuya H, Broder S (1987) Strategies for antiviral therapy in AIDS. Nature 325: 773–778

    Article  PubMed  CAS  Google Scholar 

  • Mous J, Heimer EP, Le Grice SFJ (1988) Processing protease and reverse transcriptase from human immunodeficiency virus type 1 polyprotein in Escherichia coli. J Virol 62:1433–1436

    PubMed  CAS  Google Scholar 

  • Noble S, Faulds D (1996) Saquinavir: a review of its pharmacology and clinical potential in the management of HIV infection. Drugs 52:93–112

    Article  PubMed  CAS  Google Scholar 

  • Opravil M on behalf of the SPICE Study Team (1998) Study of protease inhibitor combination in Europe (SPICE); saquinavir soft gelatin capsule (SQV-SGC) and nelfinavir in HIV infected individuals (abstract). Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago 1-5 Feb 1998, no. 394b

    Google Scholar 

  • Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338:853–860

    Article  PubMed  Google Scholar 

  • Parra R, Leal M, Delgado J, Macías J, Rubio A, Gomez F, Soriano V, Sanchez-Quijano A, Pineda JA, Lissen E (1998) Regression of invasive AIDS-related Kaposi’s sarcoma following antiretroviral therapy. Clin Infect Dis 26:218–219

    Article  PubMed  CAS  Google Scholar 

  • Pearl LH, Taylor WR (1987) A structural model for the retro viral proteases. Nature 329:351–354

    Article  PubMed  CAS  Google Scholar 

  • Popovic M, Sarngadharan MG, Read E, Gallo RC (1984) Detection and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224:497–500

    Article  PubMed  CAS  Google Scholar 

  • Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC (1980) Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Nat Acad Sci USA 77: 7415–7419

    Article  PubMed  CAS  Google Scholar 

  • Ratner L, Haseltine W, Patarca R, Livak KJ, Starcich B, Josephs SF, Doran ER, Rafalski JA, Whitehorn EA, Baumeister K, Ivanoff L, Petteway SRJR, Pearson ML, Lautenberger JA, Papas TS, Ghrayeb J, Chang NT, Gallo RC, Wong-Staal F (1985) Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature 313:277–284

    Article  PubMed  CAS  Google Scholar 

  • Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Kröhn A, Lambert RW, Merrett JM, Mills JS, Parkes KEB, Redshaw S, Ritchie AJ, Taylor DL, Thomas GJ, Machin PJ (1990) Rational design of peptide-based HIV proteinase inhibitors. Science 248:358–361

    Article  PubMed  CAS  Google Scholar 

  • Roberts NA, Craig JC, Duncan IB (1992) HIV proteinase inhibitors. Biochem Soc Trans 20:513–516

    PubMed  CAS  Google Scholar 

  • Roberts NA, Craig JC, Sheldon J (1998) Resistance and cross-resistance with saquinavir and other HIV protease inhibitors: theory and practice. AIDS 12: 453–460

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Pescador R, Power MD, Barr PJ, Steimer KS, Stempien MM, Brown-Shimer SL, Gee WW, Renard A, Randolph A, Levy JA, Dina D, Luciw PA (1985) Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science 227:484–492

    Article  PubMed  CAS  Google Scholar 

  • Sarmati L, Nicastri E, el-Sawaf G, Ventura L, Salanitro A, Ercoli L, Vella S, Andreoni M (1997)J Med Virol 53:313–318

    Article  PubMed  CAS  Google Scholar 

  • Schapiro JM, Winters MA, Stewart F, Efron B, Norris J, Kozal MJ, Merigan TC (1996) The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIVinfected patients. Ann Intern Med 124:1039–1050

    PubMed  CAS  Google Scholar 

  • Schotten C (1891) Ueber isatinblau, einen aus der Verbindung von isatin und piperidin enstehenden farbstoff. Ber Deutsch Chem Gesellschaft 24:1366–1373

    Article  Google Scholar 

  • Sension M, Farthing C, Palmer Pattison T, Pilson R, Siemon-Hryczyk P (1998) Fortovase (Saquinavir soft gel capsule, SQV-SGC) in combination with AZT and 3TC in antiretroviral-naive HIV-1 infected patients (abstract). Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago, 1-5 Feb 1998, no. 369

    Google Scholar 

  • Slater L on behalf of the NV15355 study group (1998) Activity of a new formulation of saquinavir in combination with two nucleosides in treatment naive patients (abstract). Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago 1-5 Feb 1998, no. 368

    Google Scholar 

  • Styrt BA, Piazza-Hepp TD, Chikami GK (1996) Clinical toxicity of antiretroviral nucleoside analogs. Antiviral Res 31:121–135

    Article  PubMed  CAS  Google Scholar 

  • Taylor DL, Brennan TM, Bridges CG, Kang MS, Tyms AS (1995) Synergistic inhibition of human immunodeficiency virus type 1 in vitro by 6-O-butanoylcastanospermine (MDL 28574), in combination with inhibitors of the virus encoded reverse transcriptase and proteinase. Antiviral Chem Chemother 6:143–152

    CAS  Google Scholar 

  • Toh H, Ono M, Saigo K, Miyata T (1985) Retroviral protease-like sequence in the yeast transposon. Nature 315:691–692

    Article  CAS  Google Scholar 

  • Vella S, Galluzzo C, Giannini G, Pirillo MF, Duncan I, Jacobsen H, Andreoni M, Sarmati L, Ercoli L (1996) Saquinavir/zidovudine combination in patients with advanced HIV infection and no prior antiretroviral therapy: CD4 + lymphocyte/plasma RNA changes, and emergence of strains with reduced phenotypic sensitivity. Antiviral Res 29:91–93

    Article  PubMed  CAS  Google Scholar 

  • Veronese F di M, Copeland TD, De Vico AL, Rahman R, Oroszlan S, Gallo RC, Sarngadharan MG (1986) Characterization of highly immunogenic p66/p51 as the reverse transcriptase of HTLV-III/LAV. Science 231:1289–1291

    Article  CAS  Google Scholar 

  • Williams PEO, Muihead GJ, Madigan MJ, Mitchell AM, Shaw T (1992) Disposition and bioavailability of the HIV proteinase inhibitor, Ro 31-8959, after single doses in healthy volunteers. Br J Clin Pharmacol 34:155P–156P

    Google Scholar 

  • Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278:1291–1295

    Article  PubMed  CAS  Google Scholar 

  • Zingman BS (1996) Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir. N Engl J Med 334:1674–1675

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Medicinal Chemistry II, Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, UK

    S. Redshaw & G. J. Thomas

  2. Viral Diseases, Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, UK

    N. A. Roberts

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  1. S. Redshaw
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  2. N. A. Roberts
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  3. G. J. Thomas
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Editors and Affiliations

  1. Max-von-Pettenkofer Institut für medizinische Mikrobiologie, LM Universität, LS Virologie Pettenkoferstr. 9a, D-80336, München, Germany

    Klaus von der Helm Ph.D., M.D.

  2. DuPont Pharmaceutical Co Research and Development, Edperimental Station, E336/31B, Wilmington, DE, 19880-0336, USA

    Bruce D. Korant Ph.D.

  3. Drug Discovery and Development, Source Precision Medicine, 2425 N. 55th Street, Suite 111, Boulder, CO, 80301, USA

    John C. Cheronis M.D., Ph.D. (Vice President) (Vice President)

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Redshaw, S., Roberts, N.A., Thomas, G.J. (2000). The Road to Fortovase. A History of Saquinavir, the First Human Immunodeficiency Virus Protease Inhibitor. In: von der Helm, K., Korant, B.D., Cheronis, J.C. (eds) Proteases as Targets for Therapy. Handbook of Experimental Pharmacology, vol 140. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-57092-6_1

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