An Artificially Designed Pore-forming Protein with Anti-tumor Effects*

Protein engineering is an emerging area that has expanded our understanding of protein folding and laid the groundwork for the creation of unprecedented structures with unique functions. We previously designed the first native-like pore-forming protein, small globular protein (SGP). We show here that this artificially engineered protein has membrane-disrupting properties and anti-tumor activity in several cancer animal models. We propose and validate a mechanism for the selectivity of SGP toward cell membranes in tumors. SGP is the prototype for a new class of artificial proteins designed for therapeutic applications.

[1]  Erkki Ruoslahti,et al.  Anti-cancer activity of targeted pro-apoptotic peptides , 1999, Nature Medicine.

[2]  A. Wand,et al.  De novo proteins as models of radical enzymes. , 1999, Biochemistry.

[3]  W. DeGrado,et al.  Solution structure and dynamics of a de novo designed three-helix bundle protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  H. Bayley Designed membrane channels and pores. , 1999, Current opinion in biotechnology.

[5]  Lynne Regan,et al.  The de novo design of a rubredoxin‐like fe site , 1998, Protein science : a publication of the Protein Society.

[6]  A. Krensky,et al.  Granulysin-induced apoptosis. I. Involvement of at least two distinct pathways. , 1998, Journal of immunology.

[7]  J R Desjarlais,et al.  From coiled coils to small globular proteins: Design of a native‐like three‐helix bundle , 1998, Protein science : a publication of the Protein Society.

[8]  Z. Salamon,et al.  Membrane-bound state of the colicin E1 channel domain as an extended two-dimensional helical array. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. von Heijne,et al.  Membrane-protein engineering. , 1997, Trends in biotechnology.

[10]  Shahrooz Rabizadeh,et al.  Establishment of a Cell-Free System of Neuronal Apoptosis: Comparison of Premitochondrial, Mitochondrial, and Postmitochondrial Phases , 1997, The Journal of Neuroscience.

[11]  Kevin J. Harrington,et al.  Encyclopedia of cancer, vols 1–3 , 1997 .

[12]  G. A. Lazar,et al.  De novo design of the hydrophobic core of ubiquitin , 1997, Protein science : a publication of the Protein Society.

[13]  S. Lee,et al.  De novo design, synthesis, and characterization of a pore-forming small globular protein and its insertion into lipid bilayers. , 1997, Biochemistry.

[14]  W. DeGrado,et al.  De novo design of native proteins: characterization of proteins intended to fold into antiparallel, rop-like, four-helix bundles. , 1997, Biochemistry.

[15]  M. Dathe,et al.  Hydrophobicity, hydrophobic moment and angle subtended by charged residues modulate antibacterial and haemolytic activity of amphipathic helical peptides , 1997, FEBS letters.

[16]  Virgil L. Woods,et al.  A polymeric form of fibronectin has antimetastatic effects against multiple tumor types , 1996, Nature Medicine.

[17]  E. Corey,et al.  On the failure of de novo-designed peptides as biocatalysts. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Hodges,et al.  Formation of Parallel and Antiparallel Coiled-coils Controlled by the Relative Positions of Alanine Residues in the Hydrophobic Core (*) , 1996, The Journal of Biological Chemistry.

[19]  B. Rosen,et al.  The bacterial colicin active against tumor cells in vitro and in vivo is verotoxin 1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  V. Mutt,et al.  NK‐lysin, a novel effector peptide of cytotoxic T and NK cells. Structure and cDNA cloning of the porcine form, induction by interleukin 2, antibacterial and antitumour activity. , 1995, The EMBO journal.

[21]  M. Hecht,et al.  De novo design of beta-sheet proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Richardson,et al.  Betadoublet: de novo design, synthesis, and characterization of a beta-sandwich protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Bibby,et al.  Preliminary experimental anticancer activity of cecropins. , 1994, Peptide research.

[24]  J. Levy,et al.  Characterization of a human Kaposi's sarcoma cell line that induces angiogenic tumors in animals , 1994, AIDS.

[25]  T M Handel,et al.  Metal ion-dependent modulation of the dynamics of a designed protein. , 1993, Science.

[26]  R. Kaptein,et al.  Solution structure of the POU-specific DNA-binding domain of Oct-1 , 1993, Nature.

[27]  R. Stroud,et al.  Colicin Ia inserts into negatively charged membranes at low pH with a tertiary but little secondary structural change. , 1993, Biochemistry.

[28]  A. Gazdar,et al.  Antitumor activity of magainin analogues against human lung cancer cell lines. , 1992, Cancer research.

[29]  R. Hodges,et al.  Synthetic model proteins. Positional effects of interchain hydrophobic interactions on stability of two-stranded alpha-helical coiled-coils. , 1992, The Journal of biological chemistry.

[30]  J. Lakey,et al.  A 'molten-globule' membrane-insertion intermediate of the pore-forming domain of colicin A , 1991, Nature.

[31]  J. Richardson,et al.  De novo design, expression, and characterization of Felix: a four-helix bundle protein of native-like sequence. , 1990, Science.

[32]  W. DeGrado,et al.  Protein design, a minimalist approach. , 1989, Science.

[33]  R. Cailleau,et al.  Sister chromatid exchanges and proliferation kinetics of human metastatic breast tumor cells lines. , 1982, Anticancer research.

[34]  H. Sakamoto,et al.  Study on the packing geometry, stoichiometry, and membrane interaction of three analogs related to a pore-forming small globular protein. , 2000, Biopolymers.

[35]  R. Angeletti Proteins : analysis and design , 1998 .

[36]  G Tuchscherer,et al.  Protein design: on the threshold of functional properties. , 1998, Biopolymers.

[37]  I. Pastan,et al.  Recombinant toxins as novel therapeutic agents. , 1992, Annual review of biochemistry.

[38]  J. Konisky,et al.  Colicins and other bacteriocins with established modes of action. , 1982, Annual review of microbiology.