Alternative Approach to Avoid Drug Resistance: Polyhedral Inorganic and Metallomacrobicyclic 3D‐Shaped Guests Strongly Binding to Allosteric Sites and/or Macromolecular Interfaces

Abiotic, absolutely artificial molecules of polyhedral inorganic and metallomacrobicyclic compounds are proposed as the rigid 3D-shaped platforms for the design of promising therapeutic agents binding to the allosteric sites and/or the macromolecular interfaces of suitable biotargets, in the case of which drug resistance does not occur.

Abstract

The emergence of drug resistance is one of the global problems. Prospective approach for its solution is based on the development of new and improved pharmacological principles, including the use of allosteric inhibitors of biomacromolecules and the generation of those unfolded or misfolded. Allosteric sites as hosts can be sterically blocked by rigid 3D-shaped effectors as guests. Because host bioreceptors recognize only their external surface, the nature of abiotic and artificial 3D-molecular platforms plays no important role in the supramolecular host–guest binding. Another of their modus operandi is based on blocking a surface of supramolecular interactions between biomacromolecules to cause the appearance of misfolded macromolecular assemblies or their disaggregation. 3D-shaped polyhedral inorganic and metallocomplex molecules, the periphery of which is decorated with terminal biorelevant or vector group(s), seem to be promising antitumor and antiviral drug candidates, in the case of which the emergence of drug resistance is not observed.

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