Researchers develop new method to improve the pharmacokinetic properties of macrocyclic peptides

Researchers at the Molecular Biophysics Unit (MBU) at the Indian Institute of Science (IISc) have introduced an innovative approach to enhance the pharmacokinetic properties of macrocyclic peptides, which are highly sought after by the pharmaceutical industry. By replacing a single atom (oxygen with sulfur) in the peptide’s backbone, they’ve made it more resistant to digestive enzymes and improved its ability to penetrate cell membranes, thus increasing its bioavailability.

The majority of today’s medicines are small molecules taken orally in pill form. Larger molecules like monoclonal antibodies are effective but require injection. Macrocylic peptides, which are circular structures formed by amino acid chains, offer a middle ground between small and large pharmaceutical molecules.

However, these peptides are vulnerable to digestive enzymes and struggle to cross lipid-based cell membranes due to their water-loving nature. To pass through cell membranes, they need to become more lipophilic or oil-loving, reducing their hydrogen bonding with water. Currently, N-methylation is the primary method to enhance the pharmacokinetics of macrocyclic peptides, but it can compromise their specificity.

The IISc team focused on replacing the oxygen atom in the amide bond, which interacts with water molecules, with sulfur to increase lipophilicity and reduce vulnerability to digestive enzymes.

By replacing oxygen with sulfur, they not only made the peptide more lipophilic, enhancing its ability to cross lipid membranes, but also rendered it less susceptible to digestive enzymes, which typically target the oxygen atom in the amide bond.

The team tested this modification by using a shortened version of somatostatin, a hormone that inhibits the body’s growth hormone. When injected under the skin of model animals, the modified somatostatin outperformed the unmodified version by lasting longer in the bloodstream and effectively inhibiting the growth hormone.

This innovative oxygen-to-sulfur modification approach holds promise for improving the pharmacological properties of various biologically active molecules, and it can be combined with other strategies for even better results in enhancing peptide-based drugs.

Source: Indian Institute of Science

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