Ohio State Innovation Foundation

Entrada Therapeutics, Inc.

The Ohio State University

Dehua Pei

Ziqing Qian

Punit Upadhyaya

John W Christman

Manjula Karpurapu

Patrick G Dougherty

Roger Briesewitz

Thi Trinh

Natarajan Sethuraman

George Appiah Kubi

Jason Ruth

Wenlong Lian

Lou A Tartaglia

Xianghong Wu

Louis A Tartaglia

Marina Buyanova

Disclosed herein are peptides having activity as cell penetrating peptides. In some embodiments, the peptides can comprise a cell penetrating peptide moiety and beta-haripin turn creating moiety. In other embodiments, the peptides also comprise a cargo moiety.

Cyclic cell penetrating peptides comprising beta-hairpin motifs and methods of making and using thereof

Disclosed are compounds that can penetrate the mitochondrial membrane and that are able to deliver cargo (e.g., therapeutic agents) specifically to the mitochondria.

Non-peptidic cell-penetrating motifs

Described are peptides and peptide conjugates comprising CN binding motifs (CNBM) which inhibit the CN-NFAT interaction. In some embodiments, the peptides comprise: (i) CNBM; (ii) a hydrophobic, non-peptidic moiety (RH) which interacts with the hydrophobic pocket on a CN protein; (iii) a sequence -AAU1-AAU2-AAU3-AAU4-AAU5-AAU6-, wherein each of AAU2, AAU3, AAU4, AAU5, and AAU6, is, independently, optional, and each of AAU1, AAU2, AAU3, AAU4, AAU5, and AAU6 when present is independently an amino acid as defined herein; or (iv) combinations thereof. In some embodiments, RH is conjugated to the N- or C-terminus of the CNBM. In some embodiments, the sequence -AAU1-AAU2-AAU3-AAU4-AAU5-AAU6- is conjugated to the N- or C terminus of the CNBM. In some embodiments, the peptides comprise: CNBM and RH. In some embodiments. In some embodiments, the peptides comprise: CNBM and AAU1-AAU2-AAU3-AAU4-AAU5-AAU6-. In some embodiments, the peptides of the disclosure CNBM and RH.

Peptidyl inhibitors of calcineurin-NFAT interaction

The present disclosure provides a large combinatorial library of cell-permeable bicyclic peptides. The bicyclic peptides described herein include the first ring consisted of randomized peptide sequences for potential binding to a target of interest while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the IκB kinase α/β (IKKα/β)-binding domain of NF-κB essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides which inhibited the NEMO-IKKβ interaction, thereby selectively inhibiting canonical NF-κB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells.

Bicyclic peptidyl inhibitors

The present disclosure provides for polypeptide conjugates. The polypeptide conjugates disclosed herein comprise a polyarginine peptide and a cyclic cell-penetrating peptide (cCPP) conjugated, directly or indirectly, to the polyarginine peptide. The present disclosure demonstrates that cCPPs conjugated to polyarginine peptides can be used to deliver nucleic acids to the cytosol of cells.

Polypeptide conjugates for intracellular delivery of nucleic acids

The present disclosure provides novel polypeptide conjugates. The polypeptide conjugates disclosed herein comprise a stapled peptide comprising a peptide and at least one staple which holds the peptide in an α-helical conformation, and a cyclic cell-penetrating peptide (cCPP) conjugated, directly or indirectly, to the stapled peptide. The present disclosure demonstrates that cCPPs can be used to confer consistent cell-permeability to stapled peptides.

Polypeptide conjugates for intracellular delivery of stapled peptides

Disclosed herein are novel compounds that are Ras inhibitors. Also disclosed are compositions comprising the compounds and methods of using the compounds in treating various diseases.

Small molecule Ras inhibitors

Disclosed herein are compositions and methods of treating disclosure provides for compounds for use in treating Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE). In some embodiments, the compounds have cell penetrating activity and thymidine phosphorylase activity. In certain embodiments, the compounds disclosed herein comprise: a) at least one cell-penetrating peptide (CPP) moiety; and b) a thymidine phosphorylase, or an active fragment or analog thereof (TP), wherein the CPP is coupled, directly or indirectly, to TP.

Compositions and methods for treating mitochondrial neurogastrointestinal encephalopathy

Disclosed are cell penetrating peptides and compositions comprising such peptides that can be used to deliver agents to various cell types.

Cyclic cell-penetrating peptides with one or more hydrophobic residues

Disclosed is a general, reversible bicyclization strategy to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability. Once inside the cell, the disulfide bonds are reduced to produce a linear, biologically active peptide. This strategy was applied to generate a cell-permeable bicyclic peptidyl inhibitor against the NEMO-IKK interaction.

Di-sulfide containing cell penetrating peptides and methods of making and using thereof

Anticachexin C1 inhibits the TNFα-TNFα receptor interaction. In this work, analogs of anticachexin C1 are disclosed. The resulting bicyclic peptides inhibit TNFα TNFα-induced cell death, NF-κB activation, and c-Jun N-terminal kinase (JNK) signaling in cultured mammalian cells. Methods of using the bicyclic peptide anticachexin C1 analogs to treat cancer, inflammatory disorders and immune disorders are also described.

Bicyclic peptidyl inhibitor of tumor necrosis factor-alpha

Described herein, in various embodiments, are peptides comprising: (i) a cyclic cell-penetrating peptide sequence (cCPP) and (ii) a CAL-PDZ binding sequence, which is conjugated, directly or indirectly, to an N-terminus of an amino acid in the cCPP, to a C-terminus of an amino acid on the cCPP, or on a side chain of an amino acid in the cCPP. In other embodiments, the peptides further comprise a physiologically cleavable group, wherein after entering the cell, the physiologically cleavable group is reduced, thereby providing a linear peptide. Without being bound by theory, the inventors discovered that the amino acid sequence in the cCPP, which facilities cytosolic delivery of the CAL-PDZ binding sequence also, surprisingly and unexpectedly, synergistically improves binding of CAL-PDZ binding sequence to the CAL-PDZ binding domain. Additionally, the cCPP sequence may also improve selectivity of the CAL-PDZ binding sequence for the CAL-PDZ domain relative to other PDZ binding domains.

Cyclic peptidyl inhibitors of CAL-PDZ binding domain

The present disclosure provides a large combinatorial library of cell-permeable bicyclic peptides. The bicyclic peptides described herein include the first ring consisted of randomized peptide sequences for potential binding to a target of interest while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the I&#x3ba;B kinase &#x3b1;/&#x3b2; (IKK&#x3b1;/&#x3b2;)-binding domain of NF-&#x3ba;B essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides which inhibited the NEMO-IKK&#x3b2; interaction, thereby selectively inhibiting canonical NF-&#x3ba;B signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells.

Growing community of inventors

Columbus, OH, United States of America

Dehua Pei