Current Medicinal Chemistry - Volume 11, Issue 21, 2004

This special issue reviews applications of various types of molecular constraint to bioactive molecules, especially those with therapeutic potential. Constraints are used not only for improving their pharmacological profiles, including activities and receptor specificities, of existing bioactive peptides but also to provide information on the way in which these peptides bind to their receptor and thus aid in the development of no Read More

Ligand binding and concomitant changes in receptor structure provide the means to target signal transduction pathways. With appropriate refinement of the ligand's interaction with the “receptor,” one in theory could produce ligands that have greater therapeutic benefits. This review will discuss how, when these ligands are amino acids and peptides, the introduction of appropriate conformational constraints provides Read More

Numerous backbone constraints can be used to develop pseudopeptides or pseudomimetics of biologically active peptides. Among those, N- and Cα-methyl amino acids that can be incorporated by solidphase peptide synthesis in a bioactive sequence represent important tools to restrictϕ and ψ angles of peptide backbone. This review will focus on the chemical syntheses of N- and Cα-methyl amino acids, their effects on peptid Read More

The structure-based design of peptide drugs requires the knowledge of the bioactive conformation. Studies on this receptor-bound 3D structure require linear or cyclic analogues with strongly reduced flexibility, but high biological activity, since only analogues with retained potency have preserved the bioactive conformation. Constrained amino acids containing double bonds or bulky substituents at the Nα-, Cα- and Cβ-at Read More

Restricting the conformational flexibility of medium-sized linear polypeptides is a valuable approach to identify and characterize the structural and conformational features that define their biological activities and to design analogs with enhanced agonistic or antagonistic properties and with potential therapeutic applications. The calcium-regulating and bone resorption-inhibiting hormone calcitonin (Ct) is a conformationally fl Read More

Osteogenic peptides are, or have potential to be, therapies for the treatment of osteoporosis, fracture repair, and repair of loosened bone implants. Human parathyroid hormone has been approved for the treatment of post-menopausal osteoporosis. Constrained analogs of PTH and the parathyroid-hormone related peptide (PTHrP) have aided the understanding of how PTH and PTHrP bind to their common receptor and Read More

Protein kinase C (PKC) is a family of serine / threonine kinases that regulates a variety of cell functions including proliferation, gene expression, cell cycle, differentiation, cytoskeletal organization, cell migration, and apoptosis. The PKC signal transduction cascade coordinates complex physiological events including normal tissue function and repair. Disruption of the cellular environment through genetic mutation, diseas Read More

Haemoglobinopathies differ in geographic prevalence but together are amongst the most common genetic disorders worldwide. Despite huge diagnostic progress, therapeutic options remain limited, with many treatments still at the experimental stage, no more so than in pregnancy: not only does the presence of a fetus subject treatments to greater limitations, but also any worsening of the anaemia as pregnancy progre Read More