Next-generation research shows that targeting specific Kir channels, which regulate salt reabsorption in the kidneys, could improve diuretic function in kidney patients.
The internally rectified potassium (Kir) channel 4.1/Kir5.1 could be a new drug target for diuretics, said Jerod Denton, MS, PhD, Ono Pharmaceuticals, Vanderbilt University, Nov. 5, during a session at the American Society of Nephrology Kidney Week-long Conference in Orlando, Florida.
Denton and colleagues found several structural classes of Kir4.1/Kir5.1 channel inhibitors and activators that can be used in the therapeutic setting, particularly for diuretic resistance due to salt reabsorption. These inhibitors/activators are considered “tool compounds”, but many current compounds are not commercially available.
“My lab, over the past 13 or 14 years, has developed tool compounds that expand to enhance other channels,” Denton said in his presentation, titled “Next-Generation Inward-Rectifier Potassium Channel Modulators: Discovery and molecular pharmacology”..”
These tools “provide new insights into the pharmacological mechanisms of modulating Kir channel activity in general,” Denton said.
The Kir channel is a type of potassium channel with several members in its family. These include the Kir1.1-Kir7.1 subunits—Kir 4.1 can be either homomeric or heteromeric, while Kir5.1 is heteromeric. Kirs are important because they are widely expressed in the kidneys, brain, and heart, and their role is to regulate membrane potential and ion transport.
By screening over 80,000 chemically diverse compounds, Denton first identified the Kir4.1/Kir5.1 inhibitors VU690 and VU720, which were highly selective for these potassium channels. VU720 was found to best block pores near the Kir4.1/Kir5.1 channel, with robust activation.
Further research led Denton to discover VU206, an “authentic Kir4.1/Kir5.1 activator”. VU206 observed high selectivity for these channels and increased the activity of Kir4.1/Kir5.1 mutant channels.
“We were interested to know whether or not VU206 might be able to operate and
‘rescue’ some of these mutations that have been identified,” Denton said.
An important facet in rescuing channel activity is the regulation of membrane potential. VU206 has been observed to enhance this mechanism. In these cells, Denton also indicated that the ability to modulate membrane activity is important because it can prevent patients from having too high potassium levels, which can lead to poorer outcomes for patients with kidney problems. .
Although VU720 and VU206 are 2 structurally distinct small molecules that have opposite channel activity – one inhibits activity and the other activates it – they both have the potential to better regulate potassium and sodium manipulation , thereby reducing the harmful effects that mutations can cause.
“We are using cryo-EM structural analysis to understand the molecular mechanism of action of VU720 and VU206, which apparently bind near the same location in the pore but with different binding modes,” Denton said.
The team hypothesizes that the two molecules, which bind to the same site, have unique modes that regulate activity. Both mechanisms need to be further developed to provide live benefits of molecular pharmacology.
“VU720, which we have previously released, is the first moderately potent and selective Kir4.1/Kir5.1 pore blocker,” Denton said. “We believe this work will create an enabling ‘toolbox’ for probing the integrative physiology and drug targets of Kir4.1/Kir5.1.”
Denton, Jerod. Next-Generation Inner Rectifier Potassium Channel Modulators: Discovery and Molecular Pharmacology. ASN Kidney Week. November 5, 2022. https://www.asn-online.org/education/kidneyweek/2022/program-session-details.aspx?sessId=420677