Prodrug Development

Cyclic peptides as drugs for intracellular targets: the next frontier in peptide therapeutic development Laura K. Buckton, Marwa N. Rahimi, and Shelli R. McAlpine* , Chem. Eur. J. Chem. Eur. J. V27, p1487-1513 2021 DOI:10.1002/chem.201905385

Developing macrocyclic peptides that can reach intracellular targets is a significant challenge. This review discusses the most recent strategies used to develop cell permeable cyclic peptides that maintain binding to their biological target inside the cell. Macrocyclic peptides are unique from small molecules because traditional calculated physical properties are unsuccessful for predicting cell membrane permeability. Peptide synthesis and experimental membrane permeability is the only strategy that effectively differentiates between cell permeable and cell impermeable molecules. Discussed are chemical strategies, including backbone N-methylation and stereochemical changes, which have produced molecular scaffolds with improved cell permeability. However, these improvements often come at the expense of biological activity as chemical modifications alter the peptide conformation, frequently impacting the compound’s ability to bind to the target. Highlighted is the most promising approach, which involves side chain alterations that improve cell permeability without impact binding events.

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs Yuantao Huo,Laura K. Buckton, Jack L. Bennett, Eloise C. Smith, Frances, L. Byrne, Kyle L. Hoehn, Marwa N. Rahimi, and Shelli R. McAlpine* J. Enzyme Inhib. Med. Chem.V34, p728-739, 2019 DOI: 10.1080/14756366.2019.1580276

The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell permeable peptide, which, theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, P_app, from 3.3 to 5.6, however alkyls could not be removed by liver microsomes or in-vivo and their presence decreased target binding affinity (IC₅₀ of ≥ 10 µM). Thus, unlike small molecules, peptide masking groups cannot be predictably removed; their removal is related to the 3-D conformation. O-Acetyl groups were cleaved but are labile, increasing challenges during synthesis. Utilizing acetyl groups coupled with mono-methylated amines may decrease the polarity of a peptide, while maintaining binding affinity.

Converting Polar cyclic peptides into cell permeable molecules using N-methylation Leo L. H. Lee, Laura K. Buckton* and Shelli R. McAlpine* Peptide Science, V110, e24063. 2018 DOI: 10.1002/pep2.24063

Described are the design, synthesis, and biological evaluation of 5 N-methylated analogs that are based on a lead drug structure LB51. LB51 is a cyclic pentapeptide that inhibits heat shock protein 90 and although a potent inhibitor of the protein function, it has poor cell permeability. Introduction of an N-methyl moiety at each amino acid produces 5 analogs of LB51, where all 5 show significantly improved membrane permeability over the lead molecule despite the presence of 4 highly polar side chains.

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Prodrug Development

Shelli R. McALpine, PhD., Visiting Professor at University of California, Irvine and Handling Editor Bioorganic Chemistry (Elsevier) mcalpine@uci.edu, www.coachingstemmacademics.com