Open AccessProlonging the half-life of human interferon-α2 in circulation: Design, preparation, and analysis of (2-sulfo-9-fluorenylmethoxycarbonyl)7- interferon-α2
Author(s) -
Yoram Shechter,
Liana Preciado-Patt,
Gideon Schreiber,
Mati Fridkin
Publication year - 2001
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.98.3.1212
Subject(s) - interferon , proteases , in vivo , cytokine , in vitro , alpha interferon , potency , chemistry , biological activity , chymotrypsin , biology , biochemistry , pharmacology , trypsin , enzyme , immunology , microbiology and biotechnology
Polypeptide drugs are generally short-lived species in circulation. In this study, we have covalently linked seven moieties of 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) to the amino groups of human interferon-α2. The derivative thus obtained (FMS7 –IFN-α2) has ≈4% the biological potency and 33 ± 4% the receptor binding capacity of the native cytokine. Upon incubation, FMS7 –IFN-α2 undergoes time-dependent spontaneous hydrolysis, generating active interferon witht 1/2 values of 24 ± 2 h at pH 8.5 and 98 ± 10 h at pH 7.4. When native IFN-α2 is intravenously administered to mice, circulating antiviral activity is maintained for a short duration and then declines witht 1/2 = 4 ± 0.5 h, reaching undetectable values at ≈18 h after administration. With intravenously administered FMS7 –IFN-α2, there is a lag period of 2 h, followed by a progressive elevation in circulating antiviral-active protein, which peaked at 20 h and declined witht 1/2 = 35 ± 4 h. FMS7 –IFN-α2 is resistant to α-chymotrypsin digest and to proteolytic inactivation by human serum proteasesin vitro . We have thus introduced here an inactive IFN-α2 derivative, which is resistant toin situ inactivation and has the capability of slowly reverting to the native active protein at physiological conditionsin vivo andin vitro . Having these attributes, FMS7 –IFN-α2 maintains prolonged circulating antiviral activity in mice, exceeding 7–8 times the activity of intravenously administered native cytokine.