Indian Institute of Science researchers have demonstrated a novel method for improving the pharmacokinetic properties of macrocyclic peptides – drug molecules that are pursued heavily by pharmaceutical industries worldwide.
The IISc team from the Molecular Biophysics Unit (MBU), in collaboration with Anthem Biosciences, has demonstrated that substituting just a single atom – oxygen with sulphur – in the backbone of a macrocyclic peptide can make it more resistant to digestive enzymes and can increase its permeability through cell membranes, boosting its bioavailability.
Internal environment
According to IISc, the effectiveness of any drug molecule depends on how well it interacts with the internal environment inside our body. Its pharmacokinetic properties determine how successfully it escapes degrading enzymes as it travels through the digestive system or the bloodstream, crosses biological barriers like the cell membrane, and reaches the desired target.
“A vast majority of today’s medicines are made up of small molecules taken orally as pills. Larger molecules like monoclonal antibodies are much more specific and effective but must be injected. Scientists have, therefore, turned to macrocyclic peptides, chains of amino acid residues attached to each other via amide bonds, which are engineered to form circular structures. These compounds combine the best of both small and large pharmaceutical molecules,” IISc said.
Susceptible to digestive enzymes
However, like any protein, macrocyclic peptides are highly susceptible to digestive enzymes. They also find it hard to cross cell membranes, which are made up of lipids, because they are water-loving molecules. The amide (CO-NH) bonds in these peptides interact with surrounding water molecules via relatively weaker bonds called hydrogen bonds.
“For peptides to pass through a lipid membrane, they must reduce their hydrogen bonding with water. They must become a little more oil-loving (lipophilic). Currently, there are no concrete methods besides N-methylation to improve the pharmacokinetic properties of macrocyclic peptides,” said Jayanta Chatterjee, Professor at MBU and corresponding author of the study.
Pritha Ghosh, former PhD student at MBU and first author, said that the current N-methylation strategy requires exchanging a hydrogen atom from the amide bond with a methyl group. This prevents hydrogen bond formation between the nitrogen atom from the amide bond and the surrounding water, making it easier for the peptide to pass through the lipid membrane.
However, such a modification has been shown to affect the binding of the peptide to its target by making it too flexible and less specific.
Focus on oxygen atom
To overcome this drawback, Prof. Chatterjee and his team decided instead to focus on the oxygen atom in the amide bond, which is known to interact with two water molecules via hydrogen bonds.
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