Biology subjects

Burke, M. D.

Publications and source records attributed to Burke, M. D..

4 recordsLinked to original sources

bioRxiv2025

Molecular prosthetics for CFTR designed for anion selectivity outperform amphotericin B in cultured cystic fibrosis airway epithelia

The ion channel-forming natural product amphotericin B (AmB) can serve as a molecular prosthetic for the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel and thereby restore host defenses in cultured cystic fibrosis (CF) airway epithelia. This is despite the fact that the permeability of AmB-based channels favors cations, and these channels lose their capacity to increase airway surface liquid (ASL) pH in CF airway epithelia at high concentrations. We hypothesize that modifying such channels to favor anion permeability would make them more CFTR-like and thus increase their potential therapeutic effects compared to AmB. Here we show that a synthetic derivative of AmB, AmB-AA, which has an added positively charged appendage and forms ion channels with an improved relative permeability to anions, outperformed AmB in increasing the ASL pH in CF airway epithelia at both low and high concentrations. Further modifications led to another AmB derivative, C2epiAmB-AA, that also minimized cholesterol binding and thus toxicity to cultured CF airway epithelia and was an effective surrogate for CFTR in primary cultured airway epithelia from people with CF.

pharmacology and toxicology↗

bioRxiv2025

Molecular prosthetics and CFTR modulators additively increase secretory HCO- flux in cystic fibrosis airway epithelia

Cystic Fibrosis (CF) is caused by loss-of-function mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel predominantly expressed on the apical membrane of epithelial cells. Reduced Cl- and HCO3- secretion due to dysfunctional CFTR results in a decrease in lung function and is the leading cause of morbidity in individuals with CF. Recent therapies, known as highly effective CFTR modulator therapy (HEMT), help improve the lung function in individuals with specific CF-causing mutations by enhancing the folding, trafficking, and gating of CFTR. However, variability in HEMT responsiveness leads to sub-optimal clinical outcomes in some people with CF undergoing modulator therapy. A potential strategy is to complement their function with a CFTR-independent mechanism. One possibility is the use of ion channel-forming small molecules such as amphotericin B, which has shown promise in restoring function and host defenses in CF airway disease models. Amphotericin B functions as a molecular prosthetic for CFTR and may thus complement CFTR modulators. Here we show that co-treatment of CF airway epithelia with HEMT and amphotericin B results in greater increases in both HCO3- secretory flux and ASL pH compared to treatment with either agent alone. These findings suggest that co- administration of CFTR modulators and molecular prosthetics may provide additive therapeutic benefits for individuals with CF.

pharmacology and toxicology↗

bioRxiv2023

SynerGPT: In-Context Learning for Personalized Drug Synergy Prediction and Drug Design

Predicting synergistic drug combinations can help accelerate discovery of cancer treatments, particularly therapies personalized to a patients specific tumor via biopsied cells. In this paper, we propose a novel setting and models for in-context drug synergy learning. We are given a small "personalized dataset" of 10-20 drug synergy relationships in the context of specific cancer cell targets. Our goal is to predict additional drug synergy relationships in that context. Inspired by recent work that pre-trains a GPT language model (LM) to "in-context learn" common function classes, we devise novel pre-training schemes that enable a GPT model to in-context learn "drug synergy functions". Our model--which does not use any textual corpora, molecular fingerprints, protein interaction or any other domain-specific knowledge-- is able to achieve competitive results. We further integrate our in-context approach with a genetic algorithm to optimize model prompts and select synergy candidates to test after conducting a patient biopsy. Finally, we explore a novel task of inverse drug design which can potentially enable the design of drugs that synergize specifically to target a given patients "personalized dataset". Our findings can potentially have an important impact on precision cancer medicine, and also raise intriguing questions on non-textual pre-training for LMs.

bioinformatics↗

bioRxiv2020

Small Molecule Channels Harness Membrane Potential to Concentrate Potassium in trk1Δtrk2Δ Yeast

Many protein ion channels harness membrane potential to move ions in opposition to their chemical gradient. Deficiencies of such proteins cause several human diseases, including cystic fibrosis, Bartter Syndrome Type II, and proximal renal tubular acidosis. Using yeast as a readily manipulated eukaryotic model system, we asked whether, in the context of a deficiency of such protein ion channel function in vivo, small molecule channels could similarly harness membrane potential to concentrate ions. In yeast, Trk potassium transporters use membrane potential to move potassium ions from a compartment of relatively low concentration outside cells ([~]15mM) to one of >10 times higher concentration inside (150-500mM). trk1{Delta}trk2{Delta} yeast are missing these potassium transporters and thus cannot concentrate potassium or grow in standard media. Here we show that potassium permeable, but not potassium selective, small molecule ion channels formed by the natural product amphotericin B can harness membrane potential to concentrate potassium in trk1{Delta}trk2{Delta} cells and thereby restore growth. This finding expands the list of potential human channelopathies that might be addressed by a molecular prosthetics approach.

physiology↗