Improving Pharmacokinetic Properties of Adrenocorticotropin by Site-Specific Lipid Modification

2003 ◽  
Vol 92 (9) ◽  
pp. 1882-1892 ◽  
Author(s):  
Lei Wan ◽  
Yu-Hsien Chen ◽  
Tse Wen Chang
Keyword(s):  
Lipid Modification ◽  
Site Specific ◽  
Pharmacokinetic Properties ◽  
Specific Lipid

scholarly journals Site-Specific PEGylation Enhances the Pharmacokinetic Properties and Antitumor Activity of Interferon Beta-1b

2013 ◽  
Vol 33 (12) ◽  
pp. 769-777 ◽  
Author(s):  
Ji I. Lee ◽  
Stephen P. Eisenberg ◽  
Mary S. Rosendahl ◽  
Elizabeth A. Chlipala ◽  
Jacquelyn D. Brown ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Interferon Beta ◽  
Site Specific ◽  
Pharmacokinetic Properties

ADAPTING PHARMACOKINETIC PROPERTIES OF A HUMANIZED ANTI-INTERLEUKIN-8 ANTIBODY FOR THERAPEUTIC APPLICATIONS USING SITE-SPECIFIC PEGYLATION

Cytokine ◽  
2001 ◽  
Vol 16 (3) ◽  
pp. 106-119 ◽  
Author(s):  
Steven R. Leong ◽  
Laura DeForge ◽  
Leonard Presta ◽  
Tania Gonzalez ◽  
Audrey Fan ◽  
...  
Keyword(s):  
Interleukin 8 ◽  
Site Specific ◽  
Therapeutic Applications ◽  
Pharmacokinetic Properties

scholarly journals Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation

2003 ◽  
Vol 16 (10) ◽  
pp. 761-770 ◽  
Author(s):  
K. Yang ◽  
A. Basu ◽  
M. Wang ◽  
R. Chintala ◽  
M.-C. Hsieh ◽  
...  
Keyword(s):  
Structure Function ◽  
Single Chain ◽  
Site Specific ◽  
Single Chain Fv ◽  
Pharmacokinetic Properties

scholarly journals Bacterial gasdermins reveal an ancient mechanism of cell death

2021 ◽  
Author(s):  
Alex G Johnson ◽  
Tana Wein ◽  
Megan L Mayer ◽  
Brianna Duncan-Lowey ◽  
Erez Yirmiya ◽  
...  
Keyword(s):  
Cell Death ◽  
Pore Formation ◽  
Membrane Integrity ◽  
Lipid Modification ◽  
Site Specific ◽  
Prokaryotic Cell ◽  
Inactive State ◽  
Membrane Pores ◽  
Regulated Cell Death ◽  
Peptide Release

Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. Here we discover gasdermin homologs encoded in bacteria that execute prokaryotic cell death. Structures of bacterial gasdermins reveal a conserved pore-forming domain that is stabilized in the inactive state with a buried lipid modification. We demonstrate that bacterial gasdermins are activated by dedicated caspase-like proteases that catalyze site-specific cleavage and removal of an inhibitory C-terminal peptide. Release of autoinhibition induces the assembly of >200 Å pores that form a mesh-like structure and disrupt membrane integrity. These results demonstrate that caspase-mediated activation of gasdermins is an ancient form of regulated cell death shared between bacteria and animals.

scholarly journals Site-specific incorporation of 5′-methyl DNA enhances the therapeutic profile of gapmer ASOs

2021 ◽  
Vol 49 (4) ◽  
pp. 1828-1839 ◽  
Author(s):  
Guillermo Vasquez ◽  
Graeme C Freestone ◽  
W Brad Wan ◽  
Audrey Low ◽  
Cheryl Li De Hoyos ◽  
...  
Keyword(s):  
Structural Changes ◽  
Therapeutic Potential ◽  
Therapeutic Index ◽  
Site Specific ◽  
New Era ◽  
Nucleic Acid Analogs ◽  
Pharmacokinetic Properties ◽  
Dna Modifications ◽  
Therapeutic Properties ◽  
Therapeutic Profile

Abstract We recently showed that site-specific incorporation of 2′-modifications or neutral linkages in the oligo-deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined if introducing substitution at the 5′-position of deoxynucleotide monomers in the gap can also enhance therapeutic index. Introducing R- or S-configured 5′-Me DNA at positions 3 and 4 in the oligodeoxynucleotide gap enhanced the therapeutic profile of the modified ASOs suggesting a different positional preference as compared to the 2′-OMe gap modification strategy. The generality of these observations was demonstrated by evaluating R-5′-Me and R-5′-Ethyl DNA modifications in multiple ASOs targeting HDAC2, FXI and Dynamin2 mRNA in the liver. The current work adds to a growing body of evidence that small structural changes can modulate the therapeutic properties of PS ASOs and ushers a new era of chemical optimization with a focus on enhancing the therapeutic profile as opposed to nuclease stability, RNA-affinity and pharmacokinetic properties. The 5′-methyl DNA modified ASOs exhibited excellent safety and antisense activity in mice highlighting the therapeutic potential of this class of nucleic acid analogs for next generation ASO designs.

scholarly journals Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Laurence Abrami ◽  
Tiziano Dallavilla ◽  
Patrick A Sandoz ◽  
Mustafa Demir ◽  
Béatrice Kunz ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mathematical Modelling ◽  
Experimental Determination ◽  
Kinetic Parameters ◽  
Turnover Rate ◽  
Data Driven ◽  
Lipid Modification ◽  
Site Specific

S-Palmitoylation is the only reversible post-translational lipid modification. Knowledge about the DHHC palmitoyltransferase family is still limited. Here we show that human ZDHHC6, which modifies key proteins of the endoplasmic reticulum, is controlled by an upstream palmitoyltransferase, ZDHHC16, revealing the first palmitoylation cascade. The combination of site specific mutagenesis of the three ZDHHC6 palmitoylation sites, experimental determination of kinetic parameters and data-driven mathematical modelling allowed us to obtain detailed information on the eight differentially palmitoylated ZDHHC6 species. We found that species rapidly interconvert through the action of ZDHHC16 and the Acyl Protein Thioesterase APT2, that each species varies in terms of turnover rate and activity, altogether allowing the cell to robustly tune its ZDHHC6 activity.

scholarly journals Engineering Amyloid-Like Assemblies from Unstructured Peptides via Site-Specific Lipid Conjugation

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e105641 ◽  
Author(s):  
María Pilar López Deber ◽  
David T. Hickman ◽  
Deepak Nand ◽  
Marc Baldus ◽  
Andrea Pfeifer ◽  
...  
Keyword(s):  
Site Specific ◽  
Specific Lipid

scholarly journals Cutting out the fat: Site-specific deacylation of an ion channel

2020 ◽  
Vol 295 (49) ◽  
pp. 16497-16498
Author(s):  
Pedro J. del Rivero Morfin ◽  
Manu Ben-Johny
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Bk Channels ◽  
Bk Channel ◽  
Lipid Modification ◽  
Site Specific ◽  
Channel Function ◽  
Cutting Out ◽  
And Function

S-Acylation, a reversible post-translational lipid modification of proteins, controls the properties and function of various proteins, including ion channels. Large conductance Ca2+-activated potassium (BK) channels are S-acylated at two sites that impart distinct functional effects. Whereas the enzymes that attach lipid groups are known, the enzymes mediating lipid removal (i.e. deacylation) are largely unknown. Here, McClafferty et al. identify two enzymes, ABHD17a and ABHD17c, that excise BK channel lipid groups with remarkable precision. These findings lend insights into mechanisms that orchestrate the (de)acylation that fine-tunes ion channel function in physiology and disease.

scholarly journals Identification and dynamics of the DHHC16-DHHC6 palmitoylation cascade

2017 ◽  
Author(s):  
Laurence Abrami ◽  
Tiziano Dallavilla ◽  
Patrick A. Sandoz ◽  
Mustafa Demir ◽  
Béatrice Kunz ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mathematical Modelling ◽  
Experimental Determination ◽  
Kinetic Parameters ◽  
Turnover Rate ◽  
Data Driven ◽  
Lipid Modification ◽  
Site Specific

ABSTRACTS-Palmitoylation is the only reversible post-translational lipid modification. Knowledge about the DHHC family of palmitoyltransferases is very limited. Here we show that mammalian DHHC6, which modifies key proteins of the endoplasmic reticulum, is controlled by an upstream palmitoyltransferase, DHHC16, revealing the first palmitoylation cascade. Combination of site specific mutagenesis of the three DHHC6 palmitoylation sites, experimental determination of kinetic parameters and data-driven mathematical modelling allowed us to obtain detailed information on the 8 differentially palmitoylated DHHC6 species. We found that species rapidly interconvert through the action of DHHC16 and the Acyl Protein Thioesterase APT2, that each species varies in terms of turnover rate and activity, altogether allowing the cell to robustly tune its DHHC6 activity.

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