logging in or signing up Ja FSH Receptor ACCandD Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 176 Category: Science & Tech.. License: All Rights Reserved Like it (0) Dislike it (0) Added: May 17, 2010 This Presentation is Public Favorites: 0 Presentation Description Presented by William Ja at the Alliance for Contraception in Cats & Dogs’ 4th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control, April 8-10, 2010, in Dallas, Texas, U.S. Comments Posting comment... Premium member Presentation Transcript Slide 1: William W. Ja The Scripps Research Institute Jupiter, Florida FSH receptor ligand-cytotoxin conjugates: Potential for permanent chemosterilization The Scripps Research Institute : The Scripps Research Institute Found Animals Foundation : Found Animals Foundation Found Animals Foundation : Found Animals Foundation Targeting the reproductive system : Targeting the reproductive system Grimm, 2009 Targeting the reproductive system : Targeting the reproductive system Grimm, 2009 Emanuele, 2003 Targeted cytotoxins : Targeted cytotoxins Targeting ligand Cytotoxin Targeted cytotoxins : Targeted cytotoxins Targeting ligand Cytotoxin High potency High specificity No off-target effects!! Can we target gonadal cells critical to reproduction? : Can we target gonadal cells critical to reproduction? Can we target gonadal cells critical to reproduction? : Can we target gonadal cells critical to reproduction? Can we target gonadal cells critical to reproduction? : Can we target gonadal cells critical to reproduction? gonadotropins Target: Follicle-stimulating hormone receptor : Target: Follicle-stimulating hormone receptor Wang, 2001 Gapd FSHR Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites Classical biochemistry Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites FSHR cDNA cloned Classical biochemistry Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites FSHR cDNA cloned FSH-FSHR structure Classical biochemistry FSHR: Sertoli cells : FSHR: Sertoli cells Gray’s Anatomy FSHR: Sertoli cells : FSHR: Sertoli cells Gray’s Anatomy FSHR: granulosa cells : FSHR: granulosa cells Gray’s Anatomy Sertoli & granulosa cells are crucial for reproduction : Sertoli & granulosa cells are crucial for reproduction Sertoli & granulosa cells are crucial for reproduction : Sertoli & granulosa cells are crucial for reproduction G protein-coupled receptors : G protein-coupled receptors Klaasse, 2008 G protein-coupled receptors : G protein-coupled receptors Klaasse, 2008 Accessible Drug-able Internalize FSH is a heterodimer : FSH is a heterodimer α FSHb FSHb is amenable to C-terminal conjugation : FSHb is amenable to C-terminal conjugation (PDB ID: 1XWD (Fan, 2005) FSHR ectodomain FSHa FSHb Stable mammalian cell lines : Stable mammalian cell lines Selection on hygromycin B & geneticin FSH expression : FSH expression media cells Secreted Non-secreted FSH expression : FSH expression 25 kDa media cells cells media FSHβ FSHα 20 kDa Choosing a cytotoxin : Choosing a cytotoxin Exotoxin A Diphtheria toxin Ricin Shiga toxin Cell-binding Cell-killing Choosing a cytotoxin : Choosing a cytotoxin Exotoxin A Diphtheria toxin Ricin Shiga toxin Cell-binding Cell-killing High potency Required internalization Survive proteolytic processing Economically produced (E. coli) Choosing a cytotoxin : Choosing a cytotoxin Cell-killing Target-binding Exotoxin A Diphtheria toxin Ricin Shiga toxin High potency Required internalization Survive proteolytic processing Economically produced (E. coli) Exotoxin A : Exotoxin A Cell-binding Cell-killing Translocation ADP-ribosylation I II III II III PE38 Exotoxin A entry : Exotoxin A entry Pastan, 2006 ExoA cell-killing Targeting ligand Exotoxin A : Exotoxin A Cell-binding Translocation I II III II III PE38 ADP-ribosylation Exotoxin A : Exotoxin A Cell-binding Translocation I II III II III PE38 Target-binding ADP-ribosylation Peptide “velcro” for conjugation : Peptide “velcro” for conjugation basic peptide acidic peptide O’Shea, 1993 Peptide “velcro” for conjugation : Peptide “velcro” for conjugation basic peptide acidic peptide O’Shea, 1993 SH HS Peptide “velcro” for conjugation : Peptide “velcro” for conjugation basic peptide acidic peptide O’Shea, 1993 S S PE38 for conjugation : PE38 PE38 for conjugation FSH-PE38 : II III α FSHb PE38 FSH-PE38 FSHR-FSH structure : FSHR-FSH structure (PDB ID: 1XWD (Fan, 2005) FSHR ectodomain FSHa FSHb FSHb peptide mimetics : FSHb peptide mimetics (PDB ID: 1XWD (Fan, 2005) FSHb peptide mimetics : FSHb peptide mimetics FSHb peptide mimetics : FSHb peptide mimetics Modular cytotoxin conjugates : Modular cytotoxin conjugates Modular cytotoxin conjugates : Modular cytotoxin conjugates Off-target effects: urinary tract : Off-target effects: urinary tract Control FSHR Ponglowhapan, 2007 Off-target effects: VLS : Off-target effects: VLS II III PE38 Off-target effects: VLS : Off-target effects: VLS II III PE38 Non-specific toxicity Wang, 2007 Off-target effects: VLS : Off-target effects: VLS II III PE38 Non-specific toxicity Proteolysis Immunogenicity Wang, 2007 Exotoxin A : Exotoxin A II III PE38 Wang, 2007 pDW363C Non-specific toxicity Proteolysis Immunogenicity Timeline : Timeline FSH PE38 Acknowledgments : Acknowledgments Megan Larisch (Caltech) Claudia Harden (Palm Beach Zoo) David Waugh (NCI) Found Animals Foundation wja@scripps.edu You do not have the permission to view this presentation. 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Ja FSH Receptor ACCandD Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 176 Category: Science & Tech.. License: All Rights Reserved Like it (0) Dislike it (0) Added: May 17, 2010 This Presentation is Public Favorites: 0 Presentation Description Presented by William Ja at the Alliance for Contraception in Cats & Dogs’ 4th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control, April 8-10, 2010, in Dallas, Texas, U.S. Comments Posting comment... Premium member Presentation Transcript Slide 1: William W. Ja The Scripps Research Institute Jupiter, Florida FSH receptor ligand-cytotoxin conjugates: Potential for permanent chemosterilization The Scripps Research Institute : The Scripps Research Institute Found Animals Foundation : Found Animals Foundation Found Animals Foundation : Found Animals Foundation Targeting the reproductive system : Targeting the reproductive system Grimm, 2009 Targeting the reproductive system : Targeting the reproductive system Grimm, 2009 Emanuele, 2003 Targeted cytotoxins : Targeted cytotoxins Targeting ligand Cytotoxin Targeted cytotoxins : Targeted cytotoxins Targeting ligand Cytotoxin High potency High specificity No off-target effects!! Can we target gonadal cells critical to reproduction? : Can we target gonadal cells critical to reproduction? Can we target gonadal cells critical to reproduction? : Can we target gonadal cells critical to reproduction? Can we target gonadal cells critical to reproduction? : Can we target gonadal cells critical to reproduction? gonadotropins Target: Follicle-stimulating hormone receptor : Target: Follicle-stimulating hormone receptor Wang, 2001 Gapd FSHR Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites Classical biochemistry Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites FSHR cDNA cloned Classical biochemistry Timeline : Timeline 1950 1960 1970 1980 1990 2000 Gonadotropins used to treat ovulatory dysfunction Binding of FSH to gonadal sites FSHR cDNA cloned FSH-FSHR structure Classical biochemistry FSHR: Sertoli cells : FSHR: Sertoli cells Gray’s Anatomy FSHR: Sertoli cells : FSHR: Sertoli cells Gray’s Anatomy FSHR: granulosa cells : FSHR: granulosa cells Gray’s Anatomy Sertoli & granulosa cells are crucial for reproduction : Sertoli & granulosa cells are crucial for reproduction Sertoli & granulosa cells are crucial for reproduction : Sertoli & granulosa cells are crucial for reproduction G protein-coupled receptors : G protein-coupled receptors Klaasse, 2008 G protein-coupled receptors : G protein-coupled receptors Klaasse, 2008 Accessible Drug-able Internalize FSH is a heterodimer : FSH is a heterodimer α FSHb FSHb is amenable to C-terminal conjugation : FSHb is amenable to C-terminal conjugation (PDB ID: 1XWD (Fan, 2005) FSHR ectodomain FSHa FSHb Stable mammalian cell lines : Stable mammalian cell lines Selection on hygromycin B & geneticin FSH expression : FSH expression media cells Secreted Non-secreted FSH expression : FSH expression 25 kDa media cells cells media FSHβ FSHα 20 kDa Choosing a cytotoxin : Choosing a cytotoxin Exotoxin A Diphtheria toxin Ricin Shiga toxin Cell-binding Cell-killing Choosing a cytotoxin : Choosing a cytotoxin Exotoxin A Diphtheria toxin Ricin Shiga toxin Cell-binding Cell-killing High potency Required internalization Survive proteolytic processing Economically produced (E. coli) Choosing a cytotoxin : Choosing a cytotoxin Cell-killing Target-binding Exotoxin A Diphtheria toxin Ricin Shiga toxin High potency Required internalization Survive proteolytic processing Economically produced (E. coli) Exotoxin A : Exotoxin A Cell-binding Cell-killing Translocation ADP-ribosylation I II III II III PE38 Exotoxin A entry : Exotoxin A entry Pastan, 2006 ExoA cell-killing Targeting ligand Exotoxin A : Exotoxin A Cell-binding Translocation I II III II III PE38 ADP-ribosylation Exotoxin A : Exotoxin A Cell-binding Translocation I II III II III PE38 Target-binding ADP-ribosylation Peptide “velcro” for conjugation : Peptide “velcro” for conjugation basic peptide acidic peptide O’Shea, 1993 Peptide “velcro” for conjugation : Peptide “velcro” for conjugation basic peptide acidic peptide O’Shea, 1993 SH HS Peptide “velcro” for conjugation : Peptide “velcro” for conjugation basic peptide acidic peptide O’Shea, 1993 S S PE38 for conjugation : PE38 PE38 for conjugation FSH-PE38 : II III α FSHb PE38 FSH-PE38 FSHR-FSH structure : FSHR-FSH structure (PDB ID: 1XWD (Fan, 2005) FSHR ectodomain FSHa FSHb FSHb peptide mimetics : FSHb peptide mimetics (PDB ID: 1XWD (Fan, 2005) FSHb peptide mimetics : FSHb peptide mimetics FSHb peptide mimetics : FSHb peptide mimetics Modular cytotoxin conjugates : Modular cytotoxin conjugates Modular cytotoxin conjugates : Modular cytotoxin conjugates Off-target effects: urinary tract : Off-target effects: urinary tract Control FSHR Ponglowhapan, 2007 Off-target effects: VLS : Off-target effects: VLS II III PE38 Off-target effects: VLS : Off-target effects: VLS II III PE38 Non-specific toxicity Wang, 2007 Off-target effects: VLS : Off-target effects: VLS II III PE38 Non-specific toxicity Proteolysis Immunogenicity Wang, 2007 Exotoxin A : Exotoxin A II III PE38 Wang, 2007 pDW363C Non-specific toxicity Proteolysis Immunogenicity Timeline : Timeline FSH PE38 Acknowledgments : Acknowledgments Megan Larisch (Caltech) Claudia Harden (Palm Beach Zoo) David Waugh (NCI) Found Animals Foundation wja@scripps.edu