Investigating Structural Alterations in Antagonistic Peptides for the Development of Orally Bioavailable PCSK9 Inhibitors
Abstract
Familial Hypercholesterolemia (FH) is an autosomal genetic disease that causes elevated blood levels of low-density lipoprotein (LDL). One of the leading causes of FH is gain-of-function mutations in the gene coding for proprotein convertase subtilisin/kexin type 9 (PCSK9). The PCSK9 protein binds to LDL receptors (LDLR) on the surface of hepatocytes and promotes their degradation, preventing the recycling of LDLRs and thus increasing LDL blood levels. Monoclonal antibody therapies that bind to PCSK9 inhibiting LDLR binding are currently only available as an injection. However, several orally bioavailable PCSK9 inhibitors have been formulated and are undergoing clinical trials. One such therapy contains small-molecule-peptide inhibitors that bind to a cryptic site (N-terminal groove) adjacent to the LDLR binding site located in the catalytic domain. The peptide must consist of two components: a helical peptide with a high binding affinity to PCSK9 and an appended extension with antagonistic properties to inhibit LDLR binding. Using two known PDB structures containing two unique, theorized removable peptides (A - 5VLP and B - 6U3I) in the N-terminal groove, a threedimensional printed model was created to demonstrate the interactions and proximity to a hydrophobic pocket. Through the 3D model, it was visualized that Peptide A had a beta-turn that precluded further extension into the target site, limiting its antagonistic ability. On the other hand, Peptide B’s attached organic moiety reached the hydrophobic pocket in the proximal LDLR binding region thereby increasing the binding affinity by >100 fold with reduced overall mass leading to an improved oral therapeutic.
Faculty Sponsors
Dr. Arthur Sikora, Dr. Emily Schmitt Lavin
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-5-2023 12:00 PM
End Date
4-6-2023 4:00 PM
Investigating Structural Alterations in Antagonistic Peptides for the Development of Orally Bioavailable PCSK9 Inhibitors
Alvin Sherman Library
Familial Hypercholesterolemia (FH) is an autosomal genetic disease that causes elevated blood levels of low-density lipoprotein (LDL). One of the leading causes of FH is gain-of-function mutations in the gene coding for proprotein convertase subtilisin/kexin type 9 (PCSK9). The PCSK9 protein binds to LDL receptors (LDLR) on the surface of hepatocytes and promotes their degradation, preventing the recycling of LDLRs and thus increasing LDL blood levels. Monoclonal antibody therapies that bind to PCSK9 inhibiting LDLR binding are currently only available as an injection. However, several orally bioavailable PCSK9 inhibitors have been formulated and are undergoing clinical trials. One such therapy contains small-molecule-peptide inhibitors that bind to a cryptic site (N-terminal groove) adjacent to the LDLR binding site located in the catalytic domain. The peptide must consist of two components: a helical peptide with a high binding affinity to PCSK9 and an appended extension with antagonistic properties to inhibit LDLR binding. Using two known PDB structures containing two unique, theorized removable peptides (A - 5VLP and B - 6U3I) in the N-terminal groove, a threedimensional printed model was created to demonstrate the interactions and proximity to a hydrophobic pocket. Through the 3D model, it was visualized that Peptide A had a beta-turn that precluded further extension into the target site, limiting its antagonistic ability. On the other hand, Peptide B’s attached organic moiety reached the hydrophobic pocket in the proximal LDLR binding region thereby increasing the binding affinity by >100 fold with reduced overall mass leading to an improved oral therapeutic.
