Wrapping technology

Wrapping technology is a drug-design strategy emerging in the field of molecular therapy and hinges on the basic premise that pharmaceutical drugs may be molecularly engineered to correct (wrap) the packing defects of the targeted proteins upon association.^[1][2][3] These defects take the form of solvent-exposed intramolecular hydrogen bonds, also known as dehydrons.^[4] As its name suggests, a dehydron promotes its own dehydration, thereby becoming an attractive binding site for the therapeutic drug. In turn, the water molecules in the vicinity of a dehydron are easily removable, causing epistructural tension and making dehydrons sticky. ^[5] Thus, drugs may be designed to become wrappers of dehydrons, that is they may be engineered to contribute to shield dehydrons from water attack upon association with the target. This is the operating premise behind the wrapping technology. ^[6][7][8][9]

Dehydrons can be targeted because of their physical properties and there is an addditional advantage in doing so: dehydrons are not conserved across evolutionarily related proteins. Thus, their targeting by a wrapping drug is likely to enhance the drug specificity.^[10] The evolutionary aspects of dehydron patterns are crucial to design safer wrapping drugs and have been reviewed in Nature ^[11], Scientific American ^[12], and other venues.

The biophysics background of the wrapping technology is outlined in the book Transformative Concepts for Drug Design: Target Wrapping (Springer-Verlag, Berlin, 2010, ISBN 978-3-642-11791-6).

The analysis of dehydrons was applied to re-design the drug Imatinib to attempt to reduce its side effects, with positive results demonstrated in an animal model of cancer.^[13][14]

Wrapping technology has been also used to overcome drug resistance by redesigning the parent compound ^[15]. Finally, the wrapping concept has been exploited to competitively disrupt protein-protein associations for therapeutic purposes, specifically to prevent heart failure ^[16].

References

• Ariel Fernandez's book on the biophysical basis of wrapping technology: "Transformative Concepts for Drug Design: Target Wrapping" (Springer-Verlag, Berlin, 2010, ISBN 978-3-642-11791-6)
• Review on wrapping drugs by Dr. George Demetri (Harvard Medical School)