Indian Institute of Science, Bengaluru
Indian Institute of Science researchers have demonstrated a novel methodology for enhancing the pharmacokinetic properties of macrocyclic peptides – drug molecules that are pursued closely by pharmaceutical industries worldwide.
The IISc staff from the Molecular Biophysics Unit (MBU), in collaboration with Anthem Biosciences, has demonstrated that substituting only a single atom – oxygen with sulphur – within the spine of a macrocyclic peptide can make it extra immune to digestive enzymes and can enhance its permeability via cell membranes, boosting its bioavailability.
Internal surroundings
According to IISc, the effectiveness of any drug molecule is determined by how effectively it interacts with the inner surroundings inside our physique. Its pharmacokinetic properties decide how efficiently it escapes degrading enzymes because it travels via the digestive system or the bloodstream, crosses organic boundaries just like the cell membrane, and reaches the specified goal.
“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 stated.
Susceptible to digestive enzymes
However, like all protein, macrocyclic peptides are extremely vulnerable to digestive enzymes. They additionally discover it exhausting to cross cell membranes, that are made up of lipids, as a result of they’re water-loving molecules. The amide (CO-NH) bonds in these peptides work together with surrounding water molecules through comparatively weaker bonds known as 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,” stated Jayanta Chatterjee, Professor at MBU and corresponding writer of the study.
Pritha Ghosh, former PhD scholar at MBU and first writer, stated that the present N-methylation technique 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 encircling water, making it simpler for the peptide to move via the lipid membrane.
However, such a modification has been proven to have an effect on the binding of the peptide to its goal by making it too versatile and fewer particular.
Focus on oxygen atom
To overcome this downside, Prof. Chatterjee and his staff determined as a substitute to give attention to the oxygen atom within the amide bond, which is understood to work together with two water molecules through hydrogen bonds.
