Points essentiels
L’inhibition d’une protéase ou d’une protéine de fusion est une approche générale en chimiothérapie antivirale et n’est pas spécifique du VIH. Les molécules qui provoquent ces phénomènes sont, en général, très spécifiques d’un virus ou d’une famille virale.
Dans le traitement du syndrome respiratoire aigu sévère (SRAS) liés à severe acute respiratory syndrome-Coronavirus (SARS-CoV), l’évaluation de l’efficacité des anti-VIH était essentiellement motivée par l’absence d’alternatives thérapeutiques devant un virus émergent, dans un contexte épidémique inquiétant.
Aucun des traitements commercialisés dans la prise en charge des patients vivant avec le VIH ne semble efficace dans le traitement du du SARS-CoV. Les données in vitro sont non concluantes et les données cliniques fragiles.
Des résultats préliminaires sur les inhibiteurs de protéase et les inhibiteurs d’entrée à un stade précoce de développement, très en amont des phases cliniques, ouvrent des perspectives intéressantes.
Key points
Inhibition of viral assembly (protease inhibitors) and of fusion of viral and target membranes (fusion inhibitors) are general approaches to antiviral treatment, not specific for HIV. Nonetheless, the agents that induce these phenomena are most often specific for a given virus or virus family.
Drugs developed for HIV treatment were reevaluated for use against severe acute respiratory syndrome-coronavirus (SARS-CoV) during and after the epidemic in 2003, in view of the absence of any other available treatment.
Of the protease and entry inhibitors approved for treating HIV-infected patients, none was effective against SARS-CoV, although in vitro activity against this virus was reported for the protease inhibitor lopinavir/ritonavir, in results that have not been confirmed in the most recent studies. The epidemiologic methods used to assess this drug's efficacy are not robust.
Preliminary results for SARS treatment with protease and entry inhibitors, although at early stages of development, are promising.
Références
- 1.Drosten C., Gunther S., Preiser W., van der Werf S., Brodt H.R., Becker S. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003;348:1967–1976. doi: 10.1056/NEJMoa030747. [DOI] [PubMed] [Google Scholar]
- 2.World Health Organization. Probable cases of SARS by date of onset, Worldwide, 1 November 2002-10 July 2003, 2003.
- 3.Normile D. Infectious diseases. Mounting lab accidents raise SARS fears. Science. 2004;304:659–661. doi: 10.1126/science.304.5671.659. [DOI] [PubMed] [Google Scholar]
- 4.Hsu L.Y., Lee C.C., Green J.A., Ang B., Paton N.I., Lee L. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg Infect Dis. 2003;9:713–717. doi: 10.3201/eid0906.030264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Booth C.M., Matukas L.M., Tomlinson G.A., Rachlis A.R., Rose D.B., Dwosh H.A. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801–2809. doi: 10.1001/jama.289.21.JOC30885. [DOI] [PubMed] [Google Scholar]
- 6.Larkin M. SARS treatment: who will lead the way forward? Lancet Infect Dis. 2003;3:400. doi: 10.1016/S1473-3099(03)00693-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Knowles S.R., Phillips E.J., Dresser L., Matukas L. Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada. Clin Infect Dis. 2003;37:1139–1142. doi: 10.1086/378304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Chan K.S., Lai S.T., Chu C.M., Tsui E., Tam C.Y., Wong M.M. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9:399–406. [PubMed] [Google Scholar]
- 9.Chen F., Chan K.H., Jiang Y., Kao R.Y., Lu H.T., Fan K.W. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004;31:69–75. doi: 10.1016/j.jcv.2004.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Chu C.M., Cheng V.C., Hung I.F., Wong M.M., Chan K.H., Chan K.S. Role of Lopinavir/Ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252–256. doi: 10.1136/thorax.2003.012658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Liu S., Xiao G., Chen Y., He Y., Niu J., Escalante C.R. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet. 2004;363:938–947. doi: 10.1016/S0140-6736(04)15788-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Loutfy M.R., Blatt L.M., Siminovitch K.A., Ward S., Wolff B., Lho H. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA. 2003;290:3222–3228. doi: 10.1001/jama.290.24.3222. [DOI] [PubMed] [Google Scholar]
- 13.Wu C.Y., Jan J.T., Ma S.H., Kuo C.J., Juan H.F., Cheng Y.S. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA. 2004;101:10012–10017. doi: 10.1073/pnas.0403596101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Yuan K., Yi L., Chen J., Qu X., Qing T., Rao X. Suppression of SARS-CoV entry by peptides corresponding to heptad regions on spike glycoprotein. Biochem Biophys Res Commun. 2004;319:746–752. doi: 10.1016/j.bbrc.2004.05.046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zhu J., Xiao G., Xu Y., Yuan F., Zheng C., Liu Y. Following the rule: formation of the 6-helix bundle of the fusion core from severe acute respiratory syndrome coronavirus spike protein and identification of potent peptide inhibitors. Biochem Biophys Res Commun. 2004;319:283–288. doi: 10.1016/j.bbrc.2004.04.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chen X.P., Li G.H., Tang X.P., Xiong Y., Chen X.J., Cao Y. Lack of severe acute respiratory syndrome in 19 AIDS patients hospitalized together. J Acquir Immune Defic Syndr. 2003;34:242–243. doi: 10.1097/00126334-200310010-00016. [DOI] [PubMed] [Google Scholar]
- 17.Chen X.P., Cao Y. Consideration of highly active antiretroviral therapy in the prevention and treatment of severe acute respiratory syndrome. Clin Infect Dis. 2004;38:1030–1032. doi: 10.1086/386340. [DOI] [PubMed] [Google Scholar]
- 18.Brik A., Muldoon J., Lin Y.C., Elder J.H., Goodsell D.S., Olson A.J. Rapid diversity-oriented synthesis in microtiter plates for in situ screening of HIV protease inhibitors. Chembiochem. 2003;4:1246–1248. doi: 10.1002/cbic.200300724. [DOI] [PubMed] [Google Scholar]
- 19.Wu C.Y., Chang C.F., Chen J.S., Wong C.H., Lin C.H. Rapid diversity-oriented synthesis in microtiter plates for in situ screening: discovery of potent and selective alpha-fucosidase inhibitors. Angew Chem Int Ed Engl. 2003;42:4661–4664. doi: 10.1002/anie.200351823. [DOI] [PubMed] [Google Scholar]