FDA Approved Cyclic Peptide Drugs

What is Cyclic Peptide?

Cyclic peptides are peptide chains with a cyclic structure, mostly composed of 5-14 , with a molecular weight of about 500-2000 Da. Cyclic peptides have several advantages over linear peptides. Linear peptides as drugs may be inherently unstable and have a high probability of intracellular proteolysis. Considering that the free acid and free amine are at both ends, they are also usually polar. Cyclization promotes intramolecular hydrogen bonding within the ring structure and reduces the external hydrogen bonding capacity of the molecule, which reduces the polarity of the molecule compared to the acyclic precursor and increases the membrane permeability of the compound. The two β-turn local secondary structures caused by cyclization also reduce polar surface area, which generally enhances cell permeability.

Cyclic peptides are usually produced by end-to-end, cephalic, or side-chain to side chain cyclization reactions. Introducing cyclization can make the conformation of the peptide chain more stable, thereby increasing the binding affinity to the target protein and reducing nonspecific binding due to fewer alternative conformations. Reduced conformational flexibility reduces the chance of molecules fitting to protease catalytic sites and improves proteomic resistance. Intervention in protein-protein interaction (PPI) by forming larger interaction surfaces to improve peptide chain efficacy.

Cell Permeability of Cyclic Peptides

There are three pathways by which cyclic peptides enter cells: passive diffusion pathway, carrier-mediated transport pathway, and endocytosis pathway. The passive diffusion pathway usually requires good amphiphilicity and low molecular weight (<1000Da) of cyclic peptide molecules to enter cells. Some peptide-based drugs are recognized by transporters and subsequently introduced into cells, and some cyclic peptides enter cells through PepT1 and PepT2 transporters. However, these receptors are expressed primarily in the gut (absorption) and kidney (excretion), so they are important for oral bioavailability and elimination of peptide drugs, but are unlikely to be involved in cellular penetration of target tissues. Moreover, the membrane of the endocytic sac is similar to the cell membrane, and non-passive permeable molecules may not be able to effectively escape the endosome and lysosome into the cytoplasm. In order to enhance the cell permeability of peptide drugs, it is necessary to improve the molecular weight and amphiphilicity of drugs. Cyclic peptide drugs, however, are flexible enough to meet these needs. First, controlling the sequence length of the cyclic peptide molecule can control the molecular weight requirements. Secondly, by modifying the side chains of amino acids (introducing unnatural amino acids, forming disulfide bonds, etc.) or main chains (n-methylation, etc.), introducing unnatural hydrophobic groups can enhance the hydrophobicity of cyclic peptide molecules, thus improving the cellular permeability of cyclic peptide drug molecules. Furthermore, the hydrophilic and hydrophobic properties of cyclic peptides can be further optimized according to the symmetry of the framework (d-type amino acids).

Chem. Eur. J. 2021, 27, 1487-1513

FDA Approved Cyclic Peptide Drugs

Cyclic peptide drugs targeting intracellular proteins

Romidepsin

is a natural bicyclic peptide discovered in Chromobacterium violaceum (1994), containing a head-to-tail lactone cyclization and a pair of disulfide bonds, mainly produced by fermentation. Romidepsin, a histone deacetylase inhibitor (HDACi), was approved by the FDA in 2009 for cutaneous T-cell lymphoma (CTCL) that has received at least one systemic therapy, primarily as an antineoplastic drug. It is a prodrug in which disulfide is reduced to two mercaptols in the intracellular matrix that chelates zinc ions at the zinc-dependent active site of histone deacetylase (HDAC), thereby inhibiting histone deacetylase and inducing apoptosis.