Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 36

structure of a peptide fragment with trimethylated lysine binding in the aromatic
cage pocket of CBX6 [ 21 ].
Development of compounds which emulate a natural substrate, be it for protein
inhibition or detection if a fluorescent tag is attached, is commonplace. Is it possible
to develop sensors which do the opposite—that is, mimic the binding domain of the
protein itself and sequester the substrate before it enters? Our group and others are
actively exploring this avenue of research.
2 Anion Recognition by Carboxylic Acid Bioisosteres
Since the advent of crown ethers in the 1960s, cation coordination chemistry has
been thoroughly studied and rational design of synthetic cation receptors has
matured a great deal. Anion recognition chemistry, however, had received less
attention until the 1980s. The importance of anionic species to living systems is
critical. Anions are ubiquitous in biological systems: careful regulation of intra- and
extracellular charge gradients is necessary to maintain homeostasis, and the major-
ity of enzyme substrates and cofactors carry a negative charge. DNA owes its
helical shape to well-defined hydrogen bond networks between complimentary base
pairs, phosphates provide the energy source crucial to all biochemical processes,
transport channels for small anions such as chloride and sulfate regulate the flow of
nutrients and osmotic pressure in and out the cell. Misregulation of these certain
chloride channels have been proven to cause the debilitating respiratory illness
cystic fibrosis [ 22 ], along with degenerative renal ailments Dent's disease [ 23 ] and
Bartter's syndrome [ 24 ]. Many pollutants, be it from agricultural runoff (lake
eutrophication from excess phosphate), nuclear waste (radioactive pertechnetate
discarded into the ocean), are a cause of growing environmental concern and are
anionic in nature. It is not surprising then that much attention has been focused on
creating potent receptors that are selective for anionic species of interest [ 25 - 27 ].
In biological systems, the most prominent anion present is carboxylate. Nega-
tively charged amino acids are often present at cation-binding hotspots to offer
favorable electrostatic attractions. They are also one half of the common salt-bridge
binding motif and are present in myriad enzyme substrates and cofactors. Develop-
ment of drugs and sensors that mimic these substrates often requires the creation
of esterified analogs that upon passage through a cell membrane are hydrolyzed to
the corresponding acid derivative by native esterases. An alternate strategy in drug
development is replacement of the carboxylic acid group with a functionally similar
moiety, one for which the body lacks the evolved metabolic pathways to affect
its degradation. These are known as bioisosteres of carboxylic acid. Common
acid bioisosteres include aryl sulfonamides, acyl sulfonamides, and tetrazoles
(Fig. 3 ). Utilizing these functional groups in drug development often leads
to improved oral availability, metabolic stability, and potency relative to carboxyl-
ate bearing analogs [ 28 - 30 ]. It follows that a vast number of small molecule
therapeutic targets contain tetrazole [ 31 , 32 ], aryl sulfonamide [ 33 , 34 ], and acyl
sulfonamide functionality [ 35 - 37 ].