Breaking the Wall of Drugging Ion Channels

Breaking the Wall of Drugging Ion Channels

Global Call 2025 Finalist Interview: Life Sciences    

Crina Nimigean has a degree in Physics from Bucharest University, a Ph.D. in Physiology and Biophysics from the University of Miami and postdoctoral training at Brandeis University. A world leader in ion channel structure and mechanism, she was faculty first at University of California at Davis, then Weill Cornell Medicine where she is currently a Professor. Crina Nimigean is known for her seminal work on deciphering fundamental ion channel properties such as selectivity, inactivation and lipid modulation and how small molecules can repair defective channels associated with epilepsy. 

Which wall does your research or project break? 

My project is focused on breaking the wall of drugging ion channels. Although ion channel proteins are well-established therapeutic targets for numerous diseases, developing effective drugs against them has proven challenging. Most current therapies rely on small molecules that primarily target the highly conserved ion channel pore, resulting in limited selectivity and undesirable side effects. This proposal is moving away from traditional small molecule drugs and aims to overcome these limitations by identifying selective peptide-based pore blockers that harness the channel's intrinsic self-regulatory mechanisms through pore block for therapeutic targeting. By mimicking an evolutionarily refined process, it offers a highly channel subtype specific, biologically-informed strategy to develop precise peptide-based pore-blocking drugs with reduced side effects.  

Our proposed work will also establish a framework for targeting ion channels through their intrinsic self-regulatory mechanisms as insights gained into pore-blocking peptides for our channels could be broadly applicable to other ion channels that exhibit similar self-regulation via N-terminal or intracellular domain interactions. This work addresses the urgent need for safer, more selective therapies by targeting ion channels with gain-of-function pathogenic mutations involved in neurological, cardiovascular and other diseases. By developing precise peptide-based drugs, it paves the way for treatments with fewer side effects. In the future, this strategy could transform drug discovery as it can also be applied to other ion channels with pathogenic mutations causing similar disease phenotypes, offering new hope for patients with currently untreatable conditions. This approach opens new avenues for developing selective therapeutics across a wide range of channel families. 

What is the main goal of your research or project? 

We recently discovered that human large conductance calcium-activated potassium (BK) channels self-regulate their activity through the N-terminal domain of an accessory subunit. This domain is a short, potentially unstructured peptide of 10–15 amino acids that binds to the open pore of the BK channel, effectively plugging it and halting ion flux. Our work identified the peptide's binding site within the channel and earlier studies showed that free peptides with the same sequence can similarly block the pore.  

Building on this, we aim to determine the features that confer selectivity to these peptides and develop a library of free peptides with high affinity and specificity for BK channels for potential therapeutic use. We found that the first three hydrophobic residues are essential for channel blockade. Therefore, we will design peptides of varying lengths that include these critical residues to identify the most potent blockers. Top candidates will be tested against other ion channels to isolate those that are selectively active against BK channels.  

This approach is novel as it exploits our recent discovery of the BK channel binding site's unique chemistry and harnesses the intrinsic selectivity and high affinity of its natural self-regulatory mechanism. Since this mechanism evolved specifically to modulate BK channel activity, it provides a biologically-optimised template for designing selective drugs that effectively target BK channels while minimising off-target effects—overcoming the longstanding challenge of achieving specificity in ion channel drug development. 

What advice would you give to young scientists or students interested in pursuing a career in research, or to your younger self starting in science? 

My advice to young scientists and students interested in pursuing a career in research is to forge your own path. Science advances through original thinking and bold ideas—especially from those who challenge conventions and break down walls.  

Don’t chase trends or let your curiosity be shaped too heavily by what others find interesting. Instead, focus on the questions that genuinely excite you. Push yourself to think deeply, to learn constantly and to explore new methods and techniques. Avoid getting stuck in familiar routines; innovation often lives outside your comfort zone. Ultimately, meaningful contributions will rise to the top.  

Advice I would give my younger self starting out in science is: be open to others’ help and guidance—you know less than you think and that’s okay. Don’t stay too long in toxic environments; they will drain more than they teach. Be more assertive, ask questions without hesitation and develop your confidence early. It’s not about knowing everything—it’s about growing boldly into what you don’t yet know.