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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 703 records · Page 39
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Cryo-EM structures of the small-conductance Ca 2+ -activated K Ca 2.2 channel

Small-conductance Ca 2+ -activated K + (K Ca 2.1-K Ca 2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K Ca 2.2 channel in complex with calmodulin and Ca 2+ , alone or bound to two small molecule inhibitors, at 3.18, 3.50, 2.99 and 2.97 angstrom resolution, respectively. Extracellular S3-S4 loops in β-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy’s center. Each S3-S4 β-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in the filter’s GYG signature by 180°, causing the outer selectivity filter to widen and water to enter the filter. Disruption of the tether by a mutation narrows the outer selectivity filter, realigns Tyr362 to the position seen in other K + channels, and significantly increases unitary conductance. UCL1684, a mimetic of the bee venom peptide apamin, sits atop the canopy and occludes the opening in the aromatic box. AP14145, an analogue of a therapeutic for atrial fibrillation, binds in the central cavity below the selectivity filter and induces closure of the inner gate. These structures provide a basis for understanding the small unitary conductance and pharmacology of K Ca 2.x channels.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K Ca 3.1

The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K + channel K Ca 3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K Ca 3.1 with an IC 50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K Ca 3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K Ca 3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K Ca 3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K Ca 3.1 has been experimentally confirmed as a therapeutic target.

Ong, Seow Theng [Lee Kong Chian School of Medicine↗
DOE OSTI2025

Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport

Nuclear pore complexes (NPCs) enable rapid, selective, and robust nucleocytoplasmic transport. To explain how transport emerges from the system components and their interactions, we used experimental data and theoretical information to construct an integrative Brownian dynamics model of transport through an NPC, coupled to a kinetic model of transport in the cell. The model recapitulates key aspects of transport for a wide range of molecular cargoes, including preribosomes and viral capsids. Our model quantifies how flexible phenylalanine-glycine (FG) repeat proteins create an entropic barrier to passive diffusion and how this barrier is selectively lowered in facilitated diffusion by the many transient interactions of nuclear transport receptors with the FG repeats. Selective transport is enhanced by “fuzzy” multivalent interactions, redundant FG repeat mass, coupling to the energy-dependent RanGTP concentration gradient, and exponential dependence of transport kinetics on the transport barrier. Our model will facilitate rational modulation of the NPC and its artificial mimics.

Raveh, Barak [School of Computer Science and Engin↗
DOE OSTI2026

Exploration of Nirmatrelvir Derivatives as Optimized SARS‐CoV‐2 Antivirals

Nirmatrelvir (NMV) is a SARS‐CoV‐2 antiviral component of the approved COVID‐19 therapeutic Paxlovid. It is a reversible covalent inhibitor of SARS‐CoV‐2 main protease (M Pro ) that is effluxed from human cells by P‐glycoprotein (P‐gp). To identify NMV analogs with improved potency and reduced P‐gp efflux, a structure–activity relationship campaign was conducted. Warheads alternative to nitrile for engaging the active site cysteine were tested showing aldehyde and dichloroacetamide with better enzyme inhibition potency. Crystal structure of MPI‐136−M Pro shows its aldehyde warhead forming a thiohemiacetal with active Cys145 of M Pro . Several S4 binders were explored revealing that an O‐to‐S shift at the N ‐terminal amide leads to better enzyme inhibition. By exploring different combinations of S2, S3, and S4 binders, two inhibitors with better enzyme inhibition potency than NMV were found. Crystal structure of MPI‐148, with ( S )‐2‐azaspiro[4,5]decane‐3‐carboxylate as an alternative S2 binder, shows extensive hydrogen‐bond networks for locking the inhibitor in active site, explaining high affinity of NMV analogs. Further characterization of cellular M Pro engagement and antiviral potency against SARS‐CoV‐2 revealed four inhibitors with greater potency than NMV in P‐gp‐expressing cells. Studies with the P‐gp inhibitor CP‐100356 showed that these compounds were less sensitive to P‐gp inhibition than NMV, consistent with reduced P‐gp‐mediated efflux.

Alugubelli, Yugendar R. [Texas A&M Drug Discovery ↗
DOE OSTI2025

Aromatic Amide Foldamers Show Conformation‐Dependent Electronic Properties

Electron transport in organic molecules and biomolecules is governed by electronic structure and molecular conformations. Despite recent progress, key challenges remain in understanding the role of intramolecular interactions and three-dimensional (3D) conformations on the electron transport behavior of organic molecules. In this work, the electronic properties of aromatic amide foldamers are characterized that organize into distinct 3D structures, including an extended secondary amide that adopts a trans-conformation and a folded N-methylated tertiary amide that adopts a cis-conformation. Results from single-molecule electronic experiments show that the extended secondary amide exhibits a fourfold enhancement in molecular conductance compared to the folded N-methylated tertiary amide, despite a longer contour length. The results show that extended amide molecules are governed by a through-bond electron transport mechanism, whereas folded amide molecules are dominated by through-space transport. Bulk spectroscopic characterization and density functional theory calculations further reveal that extended amides have a smaller HOMO–LUMO gap and larger transmission values compared to folded amides, consistent with single-molecule electronic experiments. Overall, this work shows that 3D molecular conformations significantly influence the electronic properties of single-molecule junctions.

electron transport↗
DOE OSTI2026

Bemnifosbuvir: An HCV NS5B Inhibitor With Multiple Modes of Action

Bemnifosbuvir (BEM) is a potent, pan-genotypic inhibitor targeting the hepatitis C virus (HCV) NS5B polymerase. Its antiviral activity was evaluated in an ascending dose phase I clinical trial involving 30 patients treated once a day for 7 days. After treatment initiation, plasma HCV RNA declined in a biphasic manner with a mean reduction of 2.3 log 10 IU/mL after 24 hours and 4.4 log10 IU/mL by day 7 for the highest dose. Alanine aminotransferase (ALT) also normalized in most patients. We employed a multiscale mathematical model fitted to the HCV RNA and ALT dynamics to quantify the antiviral activity and evaluate the modes of action of BEM. We found that models in which BEM only acted as a typical HCV RNA polymerase inhibitor and reduced the intracellular production of HCV RNA did not fit the data as well as models in which BEM had multiple modes of action, including suppressing viral assembly and secretion and enhancing intracellular HCV RNA degradation. BEM's effectiveness in inhibiting intracellular HCV RNA production increased with dose (150 mg/day: 88.2%, 300 mg/day: 98.8%, 600 mg/day: 99.5%), while inhibition of viral assembly and release was ~95% effective regardless of dose. We observed a dose-dependent enhancement in the degradation of intracellular HCV RNA, with degradation rates 1.5-fold higher in patients receiving 300 mg/day and 2.7-fold higher in those receiving 600 mg/day than in patients receiving 150 mg/day. No significant differences in antiviral activity were detected between HCV genotypes 1b and 3 or between patients with and without compensated cirrhosis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Cross‐Cultural Validation of the Binge Eating Disorder Screener‐7 ( BEDS ‐7) Across 42 Countries

ABSTRACT Objective This study aimed to evaluate the reliability and validity of the Binge Eating Disorder Screener‐7 (BEDS‐7) across 42 countries and 26 languages, assessing its reliability and validity as a screening tool for binge‐eating disorder (BED) in diverse cultural contexts. Specifically, it sought to enhance early recognition of BED symptoms in primary care settings globally, contributing to a standardized framework for assessing BED. Method The International Sex Survey, a cross‐sectional online study, was conducted in 42 countries and 26 languages. A diverse community sample of 82,243 participants, aged 18 years or older, completed the BEDS‐7 and measures of sexuality, mental health, substance use, and sociodemographic characteristics. Confirmatory factor analyses and tests of measurement invariance were employed to evaluate the reliability and validity of the BEDS‐7 across languages, countries, genders, and sexual orientations. Results The BEDS‐7 demonstrated scalar factorial invariance across languages and countries, indicating consistent factor loadings and item intercepts. In contrast, the screener showed residual invariance across gender and sexual orientation groups, supporting its robustness across these demographics. Kruskal–Wallis tests revealed significant differences in BED symptoms across languages, countries, genders, and sexual orientations, with the highest BED scores observed among queer, pansexual, and gender‐diverse individuals. The BEDS‐7 also demonstrated adequate reliability (Cronbach's alpha > 0.80) and moderate criterion validity. Discussion The findings provide further evidence of the reliability and validity of the BEDS‐7 as a potential screening tool for identifying probable cases of BED globally, facilitating early intervention in primary care settings.

Gewirtz‐Meydan, Ateret [School of Social Work, Fac↗
DOE OSTI2025

How KRAS Mutations Impair Intrinsic GTP Hydrolysis: Experimental and Computational Investigations

Oncogenic KRAS mutations impair GTP hydrolysis and increase the active GTP-bound KRAS population, which leads to growth-factor-independent cell proliferation and survival of cancer cells. Despite notable successes of small-molecule inhibitors in the treatment of KRASG12C cancer, many of these small-molecule inhibitors preferentially bind to inactive (GDP-bound) mutant KRAS, whose availability is limited by the slow rate of intrinsic GTP hydrolysis. A better understanding of how KRAS mutations impair intrinsic hydrolysis is important for designing more effective small-molecule therapeutics. In this work, experimental and computational approaches were utilized to investigate how the most important oncogenic mutations affect the intrinsic hydrolysis of GTP. Here, we found that Q61H, G12V, and G12R mutations impair intrinsic hydrolysis by around 7-fold, 9-fold, and more than 20-fold, respectively, whereas G12A, G12C, G12D, and G13D have less effect. Based on mechanistic investigations, we propose that KRAS mutations impair intrinsic hydrolysis by disrupting the interactions needed to align the nucleophilic water molecule with GTP for nucleophilic attack. These results can assist small-molecule inhibitor design and also benefit the development of other therapeutic strategies, such as rescuing hydrolysis.

Ab Initio↗
DOE OSTI2023

A Data Deposition Platform for Sharing Nuclear Magnetic Resonance Data

Nuclear magnetic resonance (NMR) data are rarely deposited in open databases, leading to loss of critical scientific knowledge. Existing data reporting methods (images, tables, lists of values) contain less information than raw data, and are poorly standardized. Together, these issues limit FAIR (findable, accessible, interoperable, reusable) access to these data, which in turn creates barriers for compound dereplication and the development of new data-driven discovery tools. Existing NMR databases are either not designed for natural products data, or employ complex deposition interfaces that disincentivize deposition. Journals, including the Journal of Natural Products (JNP), are now requiring data submission as part of the publication process, creating the need for a streamlined, user-friendly mechanism to deposit and distribute NMR data. Recently, our team reported the development of the Natural Products Magnetic Resonance Database (NP-MRD; www.np-mrd.org). Here in this paper we present a new data deposition platform for the NP-MRD project that is designed to enable users to deposit NMR data for published or submitted manuscripts in under five minutes. This platform includes a suite of automated data extraction and standardization tools, together with a simple-to-use web-based interface and detailed error reporting to simplify the data deposition process and is available at www.np-mrd.org/submissions.

96 KNOWLEDGE MANAGEMENT AND PRESERVATION↗
DOE OSTI2023

Copper-Mediated Radiobromination of (Hetero)Aryl Boronic Pinacol Esters

Herein, a copper-mediated radiobromination of (hetero)aryl boronic pinacol esters is described. Cyclotron-produced [76/77Br]bromide was isolated using an anion exchange cartridge, wherein the pre-equilibration and elution solutions played a critical role in downstream deboro-bromination. The bromination tolerates a broad range of functional groups, labeling molecules with ranging electronic and steric effects. Bologically active radiopharmaceuticals were synthesized, including two radiobrominated inhibitors of poly ADP ribose polymerase, a clinically relevant chemotherapeutic target for ovarian, breast, and prostate cancers.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Comprehensive Kinetics on the C 7 H 7 Potential Energy Surface under Combustion Conditions

The automated kinetics workflow code, KinBot, was used to explore and characterize the regions of the C 7 H 7 potential energy surface that are relevant to combustion environments and especially soot inception. We first explored the lowest-energy region, which includes the benzyl, fulvenallene + H, and cyclopentadienyl + acetylene entry points. We then expanded the model to include two higher-energy entry points, vinylpropargyl + acetylene and vinylacetylene + propargyl. The automated search was able to uncover the pathways from the literature. In addition, three important new routes were discovered: a lower-energy pathway connecting benzyl with vinylcyclopentadienyl, a decomposition mechanism from benzyl that results in side-chain hydrogen atom loss to produce fulvenallene + H, and shorter and lower energy routes to the dimethylene-cyclopentenyl intermediates. We systematically reduced the extended model to a chemically relevant domain composed of 63 wells, 10 bimolecular products, 87 barriers, and 1 barrierless channel and constructed a master equation using the CCSD(T)-F12a/cc-pVTZ//ωB97X-D/6-311++G(d,p) level of theory to provide rate coefficients for chemical modeling. Our calculated rate coefficients show excellent agreement with measured ones. We also simulated concentration profiles and calculated branching fractions from the important entry points to provide an interpretation of this important chemical landscape.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

A Prodrug Strategy to Conditionally Trap Therapeutic Payloads for Improved Tumor Retention

Altered extracellular proteolysis has been exploited to selectively activate therapeutics in diseases such as cancer; however, once activated, extracellular drugs can diffuse away, limiting efficacy. We address this challenge by coupling proteolytic activation with membrane tethering to retain drugs within diseased tissue. To accomplish this, we developed “restricted interaction peptides” (RIPs), a delivery platform that leverages elevated proteolytic activity to activate membrane-interacting peptides, localizing cargos near the site of proteolysis. We demonstrate that RIPs can deliver diverse therapeutic cargos, including cytotoxins and radioisotopes. As proof of concept, we engineered “FRIP,” a RIP designed for cleavage by fibroblast activation protein (FAP), an endoprotease upregulated in solid tumors and fibrosis. Efficient P4–P4’ substrate sequences were identified and incorporated into FRIPs. Cell-based studies showed that, upon activation, the peptide adhered to membranes rapidly internalized and successfully delivered therapeutic cargos. Consistent with this, FRIPs delivering MMAE inhibited proliferation in an FAP-dependent manner. Imaging studies confirmed tumor targeting with minimal uptake in normal tissues. Finally, FRIPs delivering MMAE or Cu-67 exhibited potent antitumor effects. These findings establish membrane tethering as a strategy to enhance drug retention.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Thermostable Enzyme Variants in the Lower Mevalonate Pathway Improve Isoprenoid Production by Cell-Free Biocatalysis

Cell-free biocatalysis is a rapidly evolving field with great potential for sustainably producing valuable chemicals. Some challenges in cell-free biocatalysis include reaction longevity, enzyme stability, and the cost of the biocatalysts. Here, the challenge of enzyme instability was addressed by employing thermophilic enzymes to improve the productivity of the lower mevalonate pathway, using limonene as an example isoprenoid product. The Classical mesophilic mevalonate pathway was compared to a newly assembled set of thermophilic enzymes comprising the Archaea I mevalonate pathway. The thermophilic pathway enzymes were thermostable to at least 60 °C and exhibited a 6× longer operating lifetime at 22 °C. Thus, despite lower initial activity rates at ambient temperature, the thermophilic pathway was longer-lived and resulted in a more productive cell-free reaction overall, achieving 1.7× higher yield of limonene compared to using enzymes from mesophiles. Moreover, the thermostable pathway retained activity for longer with the challenge of solvent exposure, namely, ethanol and isoprenol, which broadens the scope of accessible substrates and/or products in cell-free reactions employing this pathway. Altogether, we showed significant improvement in the stability and productivity of the lower mevalonate pathway, which will enable more efficient cell-free biosynthesis of isoprenoid products. This represents a valuable strategy to increase the robustness of cell-free systems by carefully sourcing biocatalysts from thermophilic organisms, which have proven to be resilient to challenges unique to cell-free reaction systems.

09 BIOMASS FUELS↗