Peptides
as a therapeutic modality attract much attention due to
their synthetic accessibility, high degree of specific binding, and
the ability to target protein surfaces traditionally considered “undruggable”.
Unfortunately, at the same time, other pharmacological properties
of a generic peptide, such as metabolic stability and cell permeability,
are quite poor, which limits the success of de novo discovered biologically active peptides as drug candidates. Here,
we review how macrocyclization as well as the incorporation of nonproteogenic
amino acids and various conjugation strategies may be utilized to
improve on these characteristics to create better drug candidates.
We analyze recent progress and remaining challenges in improving individual
pharmacological properties of bioactive peptides, and offer our opinion
on interfacing these, often conflicting, considerations, to create
balanced drug candidates as a potential way to make further progress
in this area.