Converting polar cyclic peptides into membrane permeable molecules using N‐methylation

Abstract

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.

Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A

“…Modifications of both NRPs and RiPPs significantly impact the pharmacokinetics of the respective peptide natural products. The peptides become more membrane permeable, are more resistant to proteolytic degradation and display improved target specificity, all of which enhances their applicability as therapeutic agents [10][11][12][13] .…”

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

“…We had previously reported molecules that targeted heat shock protein 90 (Hsp90), with the lead structures being LB51 and LB63 32 ,33 . However, these active inhibitors had poor cell permeability, and three approaches were used to make these molecules more effective at entering cells: masking groups 10 , d -amino acids 10 , and N -methylation 9 .…”

“…The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. The most challenging property to improve is cell permeability because structural modifications typically impact the molecule's efficacy and aqueous solubility [9][10][11][12][13][14][15] . Pioneering research has been accomplished by multiple leaders in this field 12,13,16,17 and three strategies have emerged: (1) masking polar side chains with hydrophobic moieties that can be removed within the cell, (2) incorporating D-amino acids in order to modify the conformation, and (3) N-methylating the backbone in order to alter the conformation and promote hydrophobicity 9,11,12,15 .…”

“…The most challenging property to improve is cell permeability because structural modifications typically impact the molecule's efficacy and aqueous solubility [9][10][11][12][13][14][15] . Pioneering research has been accomplished by multiple leaders in this field 12,13,16,17 and three strategies have emerged: (1) masking polar side chains with hydrophobic moieties that can be removed within the cell, (2) incorporating D-amino acids in order to modify the conformation, and (3) N-methylating the backbone in order to alter the conformation and promote hydrophobicity 9,11,12,15 . Biological studies revealed that while including D-amino acids and N-methyl groups was favourable for membrane permeability, the irreversible chemical modifications negatively impacted the bioactivity of these molecules 9,10 .…”

“…Pioneering research has been accomplished by multiple leaders in this field 12,13,16,17 and three strategies have emerged: (1) masking polar side chains with hydrophobic moieties that can be removed within the cell, (2) incorporating D-amino acids in order to modify the conformation, and (3) N-methylating the backbone in order to alter the conformation and promote hydrophobicity 9,11,12,15 . Biological studies revealed that while including D-amino acids and N-methyl groups was favourable for membrane permeability, the irreversible chemical modifications negatively impacted the bioactivity of these molecules 9,10 . In contrast, masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity.…”