Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and/or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein.

The present disclosure pertains to the field peptide stapling and/or macrocyclization, where a structural motif is used to improve the properties of amino acid sequences (e.g. protease resistance, cellular penetration, biological activity). Also within the scope of the disclosure are methods for unstapling the S,S-tetrazine-containing amino acid sequence. The disclosure is also directed to methods for the reductive removal of thiocyanates from an amino acid sequence with cysteine to recycle back to the native amino acid sequence.

The present disclosure pertains to the field peptide stapling and/or macrocyclization, where a structural motif is used to improve the properties of amino acid sequences (e.g. protease resistance, cellular penetration, biological activity). Also within the scope of the disclosure are methods for unstapling the S,S-tetrazine-containing amino acid sequence. The disclosure is also directed to methods for the reductive removal of thiocyanates from an amino acid sequence with cysteine to recycle back to the native amino acid sequence.

A method for treating opioid use disorder comprises administering to a subject a pharmaceutical composition comprising a cyclic peptide of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier; wherein the peptide of formula X.sup.1-c[X.sup.2-X.sup.3-Phe-X.sup.4]-X.sup.5 is administered in place of, and as a substitute for an opioid to which the subject is addicted. X.sup.1 is Tyr or 2,6-Dmt; X.sup.2 is an acidic or basic D-amino acid; X.sup.3 is Trp or Phe; there is an amide bond between the sidechains of X.sup.2 and X.sup.4; X.sup.5 is NHR (R=H or alkyl) or an amino acid amide. When X.sup.2 is an acidic D-amino acid, X.sup.4 is a basic amino acid, X.sup.3 is Phe, and X.sup.5 is NHR; and when X.sup.2 is a basic D-amino acid, X.sup.4 is an acidic amino acid, and X.sup.3 is Trp.

A method for treating opioid use disorder comprises administering to a subject a pharmaceutical composition comprising a cyclic peptide of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier; wherein the peptide of formula X.sup.1-c[X.sup.2-X.sup.3-Phe-X.sup.4]-X.sup.5 is administered in place of, and as a substitute for an opioid to which the subject is addicted. X.sup.1 is Tyr or 2,6-Dmt; X.sup.2 is an acidic or basic D-amino acid; X.sup.3 is Trp or Phe; there is an amide bond between the sidechains of X.sup.2 and X.sup.4; X.sup.5 is NHR (R=H or alkyl) or an amino acid amide. When X.sup.2 is an acidic D-amino acid, X.sup.4 is a basic amino acid, X.sup.3 is Phe, and X.sup.5 is NHR; and when X.sup.2 is a basic D-amino acid, X.sup.4 is an acidic amino acid, and X.sup.3 is Trp.

The present disclosure provides peptoid-based chelating ligands, corresponding cyclic peptoids, and methods of making thereof. Functional groups may be tailored for high metal binding affinity and selectivity. The side chains of a cyclic peptoid according to the present disclosure may be selected based on, for example, high affinity for actinide or other metal ions, selectivity for actinide or other metal ions, the ability to recover a metal once it is bound to the peptoid, and whether the overall peptoid should be hydrophobic or hydrophilic. Unlike siderophores, peptoid-based chelating ligands of the present disclosure are not readily hydrolyzed under physiological conditions. Therefore, peptoid-based chelating ligands may be, for example, used to treat actinide (e.g., iron and lead) poisoning in vivo. Moreover, peptoid-based chelating ligands of the present disclosure may be used for medical imaging, chelation therapy, drug delivery, and separation technologies, for example.

The present disclosure provides peptoid-based chelating ligands, corresponding cyclic peptoids, and methods of making thereof. Functional groups may be tailored for high metal binding affinity and selectivity. The side chains of a cyclic peptoid according to the present disclosure may be selected based on, for example, high affinity for actinide or other metal ions, selectivity for actinide or other metal ions, the ability to recover a metal once it is bound to the peptoid, and whether the overall peptoid should be hydrophobic or hydrophilic. Unlike siderophores, peptoid-based chelating ligands of the present disclosure are not readily hydrolyzed under physiological conditions. Therefore, peptoid-based chelating ligands may be, for example, used to treat actinide (e.g., iron and lead) poisoning in vivo. Moreover, peptoid-based chelating ligands of the present disclosure may be used for medical imaging, chelation therapy, drug delivery, and separation technologies, for example.

Described are design and generation of a set of novel cyclic lipopeptides as potential antibacterial agents. New daptomycin analogues are generated by chemical synthesis, which makes introduction of an unnatural amino acid and any modification into daptomycin possible.

Described are design and generation of a set of novel cyclic lipopeptides as potential antibacterial agents. New daptomycin analogues are generated by chemical synthesis, which makes introduction of an unnatural amino acid and any modification into daptomycin possible.

Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and/or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein.