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Myristoylation Confers Oral Bioavailability and Improves the Bioactivity of c(MyD 4-4), a Cyclic Peptide Inhibitor of MyD88

Dishon, S;Schumacher-Klinger, A;Gilon, C;Hoffman, A;Nussbaum, G;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cyclic peptide competitive inhibitor of MyD88 dimerization that is metabolically stable. Parenteral administration of c(MyD 4-4) reduces disease severity in a mouse model of the human autoimmune disease multiple sclerosis. We now show that N-terminal myristoylation of c(MyD 4-4) enhances the competitive inhibition of MyD88 dimerization in living cells, leading to improved inhibition of the Toll-like receptor and IL-1 receptor signaling. Importantly, myristoylation converts c(MyD 4-4) to an orally bioavailable inhibitor of MyD88. Oral administration of c(MyD 4-4) significantly lowered the inflammatory cytokines secreted by peripheral autoimmune T cells in mice immunized with myelin antigens and ameliorated disease severity in the mouse model of multiple sclerosis. Taken together, we show the conversion of a protein active region to a metabolically stable, selective cyclic peptide that is orally bioavailable.

PubMed ID: 30860380
351935192019-04-172019-04-1710:30:1510:30:152019-04-252019-04-2516:42:5816:42:58Dishon, S;Schumacher-Klinger, A;Gilon, C;Hoffman, A;Nussbaum, G;Dishon, S;Schumacher-Klinger, A;Gilon, C;Hoffman, A;Nussbaum, G;20192019Myristoylation Confers Oral Bioavailability and Improves the Bioactivity of c(MyD 4-4), a Cyclic Peptide Inhibitor of MyD88Myristoylation Confers Oral Bioavailability and Improves the Bioactivity of c(MyD 4-4), a Cyclic Peptide Inhibitor of MyD88Molecular PharmaceuticsMolecular Pharmaceutics1516-15221516-15221616443086038030860380

Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cyclic peptide competitive inhibitor of MyD88 dimerization that is metabolically stable. Parenteral administration of c(MyD 4-4) reduces disease severity in a mouse model of the human autoimmune disease multiple sclerosis. We now show that N-terminal myristoylation of c(MyD 4-4) enhances the competitive inhibition of MyD88 dimerization in living cells, leading to improved inhibition of the Toll-like receptor and IL-1 receptor signaling. Importantly, myristoylation converts c(MyD 4-4) to an orally bioavailable inhibitor of MyD88. Oral administration of c(MyD 4-4) significantly lowered the inflammatory cytokines secreted by peripheral autoimmune T cells in mice immunized with myelin antigens and ameliorated disease severity in the mouse model of multiple sclerosis. Taken together, we show the conversion of a protein active region to a metabolically stable, selective cyclic peptide that is orally bioavailable.

Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cyclic peptide competitive inhibitor of MyD88 dimerization that is metabolically stable. Parenteral administration of c(MyD 4-4) reduces disease severity in a mouse model of the human autoimmune disease multiple sclerosis. We now show that N-terminal myristoylation of c(MyD 4-4) enhances the competitive inhibition of MyD88 dimerization in living cells, leading to improved inhibition of the Toll-like receptor and IL-1 receptor signaling. Importantly, myristoylation converts c(MyD 4-4) to an orally bioavailable inhibitor of MyD88. Oral administration of c(MyD 4-4) significantly lowered the inflammatory cytokines secreted by peripheral autoimmune T cells in mice immunized with myelin antigens and ameliorated disease severity in the mouse model of multiple sclerosis. Taken together, we show the conversion of a protein active region to a metabolically stable, selective cyclic peptide that is orally bioavailable.

4.44.4

... Pertussis toxin (PTX, List Biological Laboratories, CA, USA) was injected intraperitoneally on the day of immunization and again after 2 days. MyR-c(MyD 4−4) was administered by gavage vs equal volume DMSO/PBS on days 0, 2, and 4. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

... Pertussis toxin (PTX, List Biological Laboratories, CA, USA) was injected intraperitoneally on the day of immunization and again after 2 days. MyR-c(MyD 4−4) was administered by gavage vs equal volume DMSO/PBS on days 0, 2, and 4. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

https://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.8b01180https://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.8b011802019-04-012019-04-0110.1021/acs.molpharmaceut.8b0118010.1021/acs.molpharmaceut.8b01180Pertussis Toxin from B. pertussis, Lyophilized in BufferPertussis Toxin from B. pertussis, Lyophilized in Buffergabrieln@ekmd.huji.ac.ilgabrieln@ekmd.huji.ac.ilActive;Autoimmune;Biological;Cyclic;Disease;IL;Inflammation;Inflammatory;Inhibitor;Intracellular;List;List Biological;Mouse;Novel;N-terminal;Peptide;Pertussis;Protein;PTX;Receptor;Response;Selective;Target;Terminal;Toxin;Molecular PharmaceuticsActive;Autoimmune;Biological;Cyclic;Disease;IL;Inflammation;Inflammatory;Inhibitor;Intracellular;List;List Biological;Mouse;Novel;N-terminal;Peptide;Pertussis;Protein;PTX;Receptor;Response;Selective;Target;Terminal;Toxin;Molecular Pharmaceutics180180myristoylation-confers-oral-bioavailability-andmyristoylation-confers-oral-bioavailability-and