Multivalent Carbonic Anhydrases Inhibitors.

Fabrizio Carta,Jean-Yves Winum,Claudiu T Supuran,Pascal Dumy

doi:10.3390/ijms20215352

Abstract

Biomolecular recognition using a multivalent strategy has been successfully applied, this last decade on several biological targets, especially carbohydrate-processing enzymes, proteases, and phosphorylases. This strategy is based on the fact that multivalent interactions of several inhibitory binding units grafted on a presentation platform may enhance the binding affinity and selectivity. The zinc metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) are considered as drug targets for several pathologies, and different inhibitors found clinical applications as diuretics, antiglaucoma agents, anticonvulsants, and anticancer agents/diagnostic tools. Their main drawback is related to the lack of isoform selectivity leading to serious side effects for all pathologies in which they are employed. Thus, the multivalent approach may open new opportunities in the drug design of innovative isoform-selective carbonic anhydrase inhibitors with biomedical applications.

Highlights

Human carbonic anhydrases are ubiquitous zinc enzymes of medical relevance that belong to the lyase family
Attaching multiple inhibitors to a molecular platform does not necessarily lead to an effective multivalent system knowing that structural parameters such as topology, structure, and valency of the platform, length and rigidity of the ligation system, are among the many parameters to be refined in order to observe and improve multivalent effects
The corresponding optical micrographs clearly visualized the preferential accumulation of gold nanorods for both HTC and MDR cell cultures incubated under hypoxia and treated with carbonic anhydrase inhibitors (CAIs)-functionalized nanorods 16 (Figure 3)

Summary

Introduction

Human carbonic anhydrases (hCA, EC 4.2.1.1) are ubiquitous zinc enzymes of medical relevance that belong to the lyase family. Small molecules approach, featuring classic medicinal chemistry and rational drug design, is still relevant and, always the subject of intense research efforts [2] Another interesting strategy that appeared recently to address the selectivity of CAIs against specific isoforms is the use of multivalent CA-directed pharmacologic agents. Attaching multiple inhibitors to a molecular platform does not necessarily lead to an effective multivalent system knowing that structural parameters such as topology, structure, and valency of the platform, length and rigidity of the ligation system, are among the many parameters to be refined in order to observe and improve multivalent effects This approach is of great interest for the medicinal chemist, in particular, for the design of enzyme inhibitors. We shall review the state of the art of the multivalent inhibition approach applied to carbonic anhydrases and its potential in both diagnostic and therapy

Nanoparticles

Gold Nanoparticles and Nanorods

Gold Nanorods

Conclusions and Prospects