Biology subjects

Lubell, W. D.

Publications and source records attributed to Lubell, W. D..

4 recordsLinked to original sources

bioRxiv2026

A peptidomimetic inhibitor blocks Vibrio cholerae adhesin FrhA.

Cholera is a diarrheal disease from colonization of the small intestine by the Gram-negative bacterium Vibrio cholerae. Cholera remains a critical public health concern due to limitations in therapy and rising antibiotic resistance. The peptide-binding domain (PBD) of the adhesion protein FrhA is critical for V. cholerae intestinal colonization and biofilm formation. In a program targeted on blocking cholera infection, antagonists of the FrhA-PBD are described based on a tripeptide motif. Notably, constraint of the N-terminal tryptophan residue using 1,2,3,4-tetrahydro-{beta}-carboline-3-carboxylic acid (Tcc) and co-crystallization of H-(S)-Tcc-Thr-Asp-OH with an FrhA construct has provided structural information to guide inhibitor design. The diastereomer (R)-Tcc-Thr-Asp exhibited nanomolar binding affinity (Kd = 101 {+/-} 30.2 nM). H-(R)-Tcc-Thr-Asp-OH blocked bacterial hemagglutination mediated by FrhA-PBD and reduced biofilm formation in vitro. Moreover, it showed greater resistance to the digestive enzyme chymotrypsin than previously reported inhibitory pentapeptides, offering potential proteolytic stability while blocking FrhA-PBD-mediated adhesion in the intestine.

biochemistry↗

bioRxiv2026

CD36 phosphorylation alters the thrombospondin binding site and reduces internal cavity accessibility and volume

The cluster of differentiation 36 (CD36) is a membrane protein with broad physiological roles in health and disease, and its function is regulated in part by phosphorylation. Experimental evidence shows that phosphorylation of Thr92 reduces CD36 affinity for thrombospondin-1 (TSP-1), binding of which initiates antiangiogenic signaling, whereas phosphorylation of Ser237 decreases CD36-mediated fatty acid uptake, with implications for energy metabolism. However, the only available crystal structure of CD36 lacks phosphorylation, and the molecular mechanisms by which phosphorylation regulates CD36 function remain largely unknown. This study provides an atomically detailed computational characterization of CD36 in unphosphorylated and dual phosphorylated states, using molecular dynamics simulations with a total sampling time of 30 microseconds in combination with Markov state models. We present, to our knowledge, the first evidence of a cryptic pocket on CD36 surface that is formed by phosphorylation. This cryptic surface pocket and a loop spanning residues 121-131 form a high affinity binding site for TSP-1 derived ligands, shifting their binding away from the canonical site. We propose that this altered binding provides a molecular basis for the disruption of antiangiogenic signaling upon CD36 phosphorylation. Additionally, our data indicate that, phosphorylation increases helicity and compaction within the helix-loop region spanning residues 296-331, narrowing one of the entrances to the internal cavity and reducing its overall volume. These conformational changes provide a potential mechanistic explanation for the decrease in fatty acid uptake upon CD36 phosphorylation. Our findings provide structural insights that may inform the future design of CD36 modulators and emphasize the importance of targeting phosphorylation induced CD36 conformations in angiogenic and metabolic diseases.

biophysics↗

bioRxiv2025

Cyclic azapeptide cluster of differentiation-36 receptor modulator attenuates left ventricular injury and temporarily reduces long-chain fatty acid accumulation after myocardial ischemia-reperfusion in mice

Ischemic heart disease remains a leading global cause of death. We investigated the cardio-protective effects of the selective cluster of differentiation-36 receptor (CD36) modulator azapeptide MPE-298 in a mouse model of myocardial ischemia-reperfusion. Before reperfusion, a single intravenous dose of azapeptide MPE-298 reduced infarct size by 37% and transiently decreased left ventricular (LV) long-chain fatty acid (LCFA) accumulation, independently of saturation status. Metabolomic profiling revealed shifts in amino acids involved in energy production and antioxidant defense. Gene expression analysis showed transient modulation of oxidative stress and inflammation in both heart and adipose tissue. Modulation of CD36 by azapeptide MPE-298 exhibited therapeutic potential for treating acute myocardial ischemia and reperfusion by supporting metabolic recovery and limiting excess LCFA uptake. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/674351v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11aa899org.highwire.dtl.DTLVardef@132fc5borg.highwire.dtl.DTLVardef@55c32forg.highwire.dtl.DTLVardef@81585f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Peptide-based ligand antagonists block a Vibrio cholerae adhesin

Vibrio cholerae, the causative agent of cholera, uses surface proteins such as the repeats-in-toxin (RTX) adhesin FrhA to colonize hosts and initiate infection. Blocking bacterial adhesion represents a promising therapeutic strategy to treat infections without promoting drug resistance. FrhA contains a peptide-binding domain (PBD) that is key for hemagglutination, human epithelial cell binding, and V. cholerae biofilm formation. Previous studies identified a lead pentapeptide ligand with the sequence Ala-Gly-Tyr-Thr-Asp (AGYTD) that blocks V. cholerae colonization of the mouse small intestine at high micromolar concentrations. A structure-guided approach has now identified a minimal D-amino acid-containing tripeptide motif with higher affinity for the FrhA-PBD and predicted metabolic stability. Our results contribute to the development of anti-adhesion strategies to combat infections.

microbiology↗