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J Virol. May 1995; 69(5): 3206–3210.
PMCID: PMC189026

Engineered serine protease inhibitor prevents furin-catalyzed activation of the fusion glycoprotein and production of infectious measles virus.


We have identified the major cellular endoprotease that activates the fusion (F) glycoprotein of measles virus (MV) and have engineered a serine protease inhibitor (serpin) to target the endoprotease and inhibit the production of infectious MV. The F-protein precursor of MV was not cleaved efficiently into the mature F protein in human colon carcinoma cells lacking functional furin, indicating that furin is the major enzyme responsible for activation of the MV F protein. A human serpin alpha 1-antitrypsin variant was engineered to specifically inhibit furin. When expressed from a recombinant vaccinia virus in primate cells infected by MV, the engineered serpin (alpha 1-PDX) specifically inhibited furin-catalyzed cleavage of the F-protein precursor without affecting synthesis of other MV proteins. We generated human glioma cells stably expressing alpha 1-PDX. MV infection in these cells did not result in syncytia. The infected cells produced all the MV proteins, but the F-protein precursor remained largely uncleaved. This did not prevent virus assembly. However, the released virions contained inactive F-protein precursor rather than mature F protein, and infectious-virus titers were reduced by 3 to 4 orders of magnitude. These results show that a mature F protein is not required for the assembly of MV but is crucial for virus infectivity. The engineered serpin may offer a novel molecular antiviral approach against MV.

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Selected References

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  • Alkhatib G, Shen SH, Briedis D, Richardson C, Massie B, Weinberg R, Smith D, Taylor J, Paoletti E, Roder J. Functional analysis of N-linked glycosylation mutants of the measles virus fusion protein synthesized by recombinant vaccinia virus vectors. J Virol. 1994 Mar;68(3):1522–1531. [PMC free article] [PubMed]
  • Anderson ED, Thomas L, Hayflick JS, Thomas G. Inhibition of HIV-1 gp160-dependent membrane fusion by a furin-directed alpha 1-antitrypsin variant. J Biol Chem. 1993 Nov 25;268(33):24887–24891. [PubMed]
  • Bresnahan PA, Leduc R, Thomas L, Thorner J, Gibson HL, Brake AJ, Barr PJ, Thomas G. Human fur gene encodes a yeast KEX2-like endoprotease that cleaves pro-beta-NGF in vivo. J Cell Biol. 1990 Dec;111(6 Pt 2):2851–2859. [PMC free article] [PubMed]
  • Decroly E, Vandenbranden M, Ruysschaert JM, Cogniaux J, Jacob GS, Howard SC, Marshall G, Kompelli A, Basak A, Jean F, et al. The convertases furin and PC1 can both cleave the human immunodeficiency virus (HIV)-1 envelope glycoprotein gp160 into gp120 (HIV-1 SU) and gp41 (HIV-I TM). J Biol Chem. 1994 Apr 22;269(16):12240–12247. [PubMed]
  • Gotoh B, Ohnishi Y, Inocencio NM, Esaki E, Nakayama K, Barr PJ, Thomas G, Nagai Y. Mammalian subtilisin-related proteinases in cleavage activation of the paramyxovirus fusion glycoprotein: superiority of furin/PACE to PC2 or PC1/PC3. J Virol. 1992 Nov;66(11):6391–6397. [PMC free article] [PubMed]
  • Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W. Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature. 1992 Nov 26;360(6402):358–361. [PubMed]
  • Hirano A. Subacute sclerosing panencephalitis virus dominantly interferes with replication of wild-type measles virus in a mixed infection: implication for viral persistence. J Virol. 1992 Apr;66(4):1891–1898. [PMC free article] [PubMed]
  • Hosaka M, Nagahama M, Kim WS, Watanabe T, Hatsuzawa K, Ikemizu J, Murakami K, Nakayama K. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. J Biol Chem. 1991 Jul 5;266(19):12127–12130. [PubMed]
  • Matheson NR, van Halbeek H, Travis J. Evidence for a tetrahedral intermediate complex during serpin-proteinase interactions. J Biol Chem. 1991 Jul 25;266(21):13489–13491. [PubMed]
  • Misumi Y, Oda K, Fujiwara T, Takami N, Tashiro K, Ikehara Y. Functional expression of furin demonstrating its intracellular localization and endoprotease activity for processing of proalbumin and complement pro-C3. J Biol Chem. 1991 Sep 5;266(25):16954–16959. [PubMed]
  • Molloy SS, Bresnahan PA, Leppla SH, Klimpel KR, Thomas G. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. J Biol Chem. 1992 Aug 15;267(23):16396–16402. [PubMed]
  • Molloy SS, Thomas L, VanSlyke JK, Stenberg PE, Thomas G. Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. EMBO J. 1994 Jan 1;13(1):18–33. [PMC free article] [PubMed]
  • Morikawa Y, Barsov E, Jones I. Legitimate and illegitimate cleavage of human immunodeficiency virus glycoproteins by furin. J Virol. 1993 Jun;67(6):3601–3604. [PMC free article] [PubMed]
  • Nagai Y. Protease-dependent virus tropism and pathogenicity. Trends Microbiol. 1993 Jun;1(3):81–87. [PubMed]
  • Ohnishi Y, Shioda T, Nakayama K, Iwata S, Gotoh B, Hamaguchi M, Nagai Y. A furin-defective cell line is able to process correctly the gp160 of human immunodeficiency virus type 1. J Virol. 1994 Jun;68(6):4075–4079. [PMC free article] [PubMed]
  • Owen MC, Brennan SO, Lewis JH, Carrell RW. Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder. N Engl J Med. 1983 Sep 22;309(12):694–698. [PubMed]
  • Perlmutter DH, Pierce JA. The alpha 1-antitrypsin gene and emphysema. Am J Physiol. 1989 Oct;257(4 Pt 1):L147–L162. [PubMed]
  • Rehemtulla A, Barr PJ, Rhodes CJ, Kaufman RJ. PACE4 is a member of the mammalian propeptidase family that has overlapping but not identical substrate specificity to PACE. Biochemistry. 1993 Nov 2;32(43):11586–11590. [PubMed]
  • Richardson C, Hull D, Greer P, Hasel K, Berkovich A, Englund G, Bellini W, Rima B, Lazzarini R. The nucleotide sequence of the mRNA encoding the fusion protein of measles virus (Edmonston strain): a comparison of fusion proteins from several different paramyxoviruses. Virology. 1986 Dec;155(2):508–523. [PubMed]
  • Sato TA, Kohama T, Sugiura A. Intracellular processing of measles virus fusion protein. Arch Virol. 1988;98(1-2):39–50. [PubMed]
  • Stieneke-Gröber A, Vey M, Angliker H, Shaw E, Thomas G, Roberts C, Klenk HD, Garten W. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J. 1992 Jul;11(7):2407–2414. [PMC free article] [PubMed]
  • Takahashi S, Kasai K, Hatsuzawa K, Kitamura N, Misumi Y, Ikehara Y, Murakami K, Nakayama K. A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1019–1026. [PubMed]
  • Tulchinsky TH, Ginsberg GM, Abed Y, Angeles MT, Akukwe C, Bonn J. Measles control in developing and developed countries: the case for a two-dose policy. Bull World Health Organ. 1993;71(1):93–103. [PMC free article] [PubMed]
  • Walker JA, Molloy SS, Thomas G, Sakaguchi T, Yoshida T, Chambers TM, Kawaoka Y. Sequence specificity of furin, a proprotein-processing endoprotease, for the hemagglutinin of a virulent avian influenza virus. J Virol. 1994 Feb;68(2):1213–1218. [PMC free article] [PubMed]
  • Weiss R. Measles battle loses potent weapon. Science. 1992 Oct 23;258(5082):546–547. [PubMed]
  • Wong TC, Ayata M, Ueda S, Hirano A. Role of biased hypermutation in evolution of subacute sclerosing panencephalitis virus from progenitor acute measles virus. J Virol. 1991 May;65(5):2191–2199. [PMC free article] [PubMed]

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