Journal
PHARMACEUTICS
Volume 14, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics14102102
Keywords
CNG channels; retinal degeneration; target selectivity; Retinitis pigmentosa; ion channels; cGMP analogues; drug therapy
Categories
Funding
- Deutsche Forschungsgemeinschaft [TRR 166, B01, 437036164, PA1751/8-1]
- Hector Fellow Grant [HFA-WH-2020]
- Kerstan Foundation [KF-WH-2019]
- BMBF [16GW0267K]
- European Union [DRUGSFORD: HEALTH-F2-2012-304963]
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This study presents a novel strategy to selectively modulate the activity of rod or cone photoreceptors using cGMP analogues with opposing actions. This strategy may address the issue of isoform-specificity in pharmacological therapies and improve visual performance in certain light environments.
The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments.
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