Making a Match for Valinomycin: Steroidal Scaffolds in the Design of Electroneutral, Electrogenic Anion Carriers

Hennie Valkenier, Anthony P. Davis*

*Corresponding author for this work

Research output: Contribution to journalReview article (Academic Journal)peer-review

80 Citations (Scopus)

Abstract

The natural product Valinomycin is a well-known transmembrane cation carrier. Despite being uncharged, this molecule can extract potassium ions from water without counterions and ferry them through a membrane interior. Because it only transports positive ions, it is electrogenic, mediating a flow of charge across the membrane. Equivalent agents for anions would be valuable research tools and may have therapeutic applications, especially in the treatment of "channelopathies" such as cystic fibrosis. However, no such molecules have been found in nature.

In this Account, we describe our research toward synthetic and rationally designed "anti- Valinomycins". As our core approach to this problem, we used the steroid nucleus, provided by cholic add, as a scaffold for the assembly of anion receptors. By positioning H-bond donors on this framework, especially urea and thiourea groups in conformationally constrained axial positions, we created binding sites capable of exceptionally high affinities (up to 10(11) M-1 for R4N+Cl- in chloroform). The extended hydrocarbon surface of the steroid helped to maintain compatibility with nonpolar media. When we tested these "cholapods" for chloride transport in vesicles, they provided the first evidence for electrogenic anion transport mediated by electroneutral organic carriers: in other words, they are the first authenticated anti-Valinomycins. They also proved active in live cells that we grew and assayed in an Ussing chamber.

In subsequent work, we have shown that the cholapods can exhibit very high activities, with transport observed down to carrier/lipid ratios of 1:250000. We also understand some of the effects of structure on the activity of these molecules. For example, in most cases, powerful transporters also act as powerful receptors. On the other hand, some modifications which favor binding do not promote transport. We gained functional advantages by cyclizing the cholapod architecture, which encloses the anion binding site. We could also simplify the structure without compromising function. A steroid-inspired trans-decalin framework has proved highly effective and may lead to agents with practical advantages. Changing an ester side-chain in this system revealed a surprising effect, whereby increased length and/or lipophilicity resulted in substantially raised activity. Although much remains to be discovered about these anionophores, their high activities and intrinsic tuneabilities bode well for applications. In future work, we plan to develop and exploit these molecules as tools for biophysical research and to explore the possibility of useful biological activity.

Original languageEnglish
Pages (from-to)2898-2909
Number of pages12
JournalAccounts of Chemical Research
Volume46
Issue number12
DOIs
Publication statusPublished - 17 Dec 2013

Keywords

  • CHLORIDE TRANSPORT
  • TRIAMINO-ANALOG
  • SUPRAMOLECULAR CHEMISTRY
  • NEUTRAL ANIONOPHORES
  • METHYL CHOLATE
  • ION-TRANSPORT
  • CHOLIC-ACID
  • FLIP-FLOP
  • RECEPTORS
  • COMPLEXATION

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