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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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All sourcesNASA NTRSDOE OSTI
NASA NTRS1975

Launch, flight, and recovery

The final phase to fly five pocket mice in the Apollo XVII command module was carried out at the NASA Kennedy Space Center. Upon completion of the 13-d space flight, the package was removed from the spacecraft and, after having been purged with an oxygen-helium gas mixture, was flown to American Samoa. Four of the five mice were recovered alive from the package. Analysis of the mouse that died during the flight revealed several factors that could have contributed to its death, the chief of which was massive hemorrhage in its middle ear cavities.

Look, B. C.↗
NASA NTRS1975

Cosmic ray particle dosimetry and trajectory tracing

Five pocket mice (Perognathus longimembris) were flown on Apollo XVII, each with a solid-state (plastic) nuclear track detector implanted beneath its scalp. The subscalp detectors were sensitive to HZE cosmic ray particles with a LET greater than or approximately equal to 0.15 million electron volts per micrometer (MeV/micron). A critical aspect of the dosimetry of the experiment involved tracing individual particle trajectories through each mouse head from particle tracks registered in the individual subscalp detectors, thereby establishing a one-to-one correspondence between a trajectory location in the tissue and the presence or absence of a lesion. The other major aspect was the identification of each registered particle. An average of 16 particles with Z greater than or equal to 6 and 2.2 particles with Z greater than or equal to 20 were found per detector. The track density, 29 tracks/sq cm, when adjusted for detection volume, was in agreement with the photographic emulsion data from an area dosimeter located next to the flight package.

Cruty, M. R.↗
DOE OSTI2025

S -Adenosylhomocysteine Analogs Selectively Suppress Pan-Coronavirus Replication by Inhibition of nsp14 Methyltransferase

To address the ongoing threat of SARS-CoV-2 and potential emergence of novel coronaviruses, we employed a comprehensive strategy to identify and synthesize inhibitors of coronavirus methyltransferases with chemical analogs of S-adenosylhomocysteine (SAH). Two analogs, designated 4h and 4p, inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound 4p was the most potent with half-maximal inhibition of biochemical activity at 0.2 μM and antiviral activity at ∼20 μM. This compound also has low cytotoxicity and preferentially inhibits nsp14 over nsp16 and human methyltransferases. Furthermore, molecular docking based on a newly determined crystal structure of the apo nsp16−nsp10 complex predicts that 4p occupies both the Sadenosylmethione and Gppp binding pockets of nsp14 and nsp16. Selectivity of 4p for nsp14 is likely due to the enhanced structural stability of the nsp14 binding pocket relative to nsp16. These findings highlight SAH analogs as scaffolds for pan-coronavirus therapeutics and underscore the value of structure-guided design in antiviral drug discovery.

Coronavirus↗
DOE OSTI2023

Ultrafast structural changes direct the first molecular events of vision

Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs). A photon is absorbed by the 11-cis retinal chromophore of rhodopsin, which isomerizes within 200 femtoseconds to the all-transconformation, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains experimentally unclear. Here we use ultrafast time-resolved crystallography at room temperature to determine how an isomerized twisted all-trans retinal stores the photon energy that is required to initiate the protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at a 1-ps time delay after photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Notably, the very early structural motions in the protein side chains of rhodopsin appear in regions that are involved in later stages of the conserved class A GPCR activation mechanism. Our study sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding

Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2 -/- and Spdya -/- phenotypes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Oxamniquine derivatives overcome Praziquantel treatment limitations for Schistosomiasis

Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 μM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 μM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Structural Mechanism of an Efficacy Photoswitch Targeting the β 2 ‐adrenergic Receptor

The field of photopharmacology develops light-responsive drugs that can modulate protein activity, enabling precise and dynamic investigations of their roles in health and disease. Adrenergic receptors are prominent targets for this approach because they are prototypical G protein-coupled receptors with high clinical relevance in bronchial and cardiovascular diseases. Here, we employed the azobenzene-based compound photoazolol-1 in combination with time-resolved serial crystallography at X-ray free-electron lasers to resolve the molecular mechanisms by which photoswitchable β-blockers modulate activity of the β 2 -adrenoceptor (β 2 AR). Time-resolved structures of the receptor bound to trans-photoazolol-1 (pre-photoconversion), a strained intermediate in the nanosecond range, and the fully photoisomerized cis-photoazolol-1 reveal how isomerization of the azobenzene moiety induces distinct conformational changes within the orthosteric ligand binding pocket. Within seconds, light-excited photoazolol-1 adopts a new binding pose, altering interactions with extracellular loop 2 and shifting the positions of transmembrane helices 5, 6, and 7. Functional assays of β 2 AR in cellular membranes show that photoazolol-1 acts as an efficacy photoswitch, changing from an inverse agonist to a neutral antagonist upon isomerization without leaving the binding pocket. In combination, these findings suggest a molecular mechanism for activity modulation via efficacy photoswitches and provide a framework for designing ligands that exploit light-driven transitions within the binding pocket to achieve spatiotemporal control of receptor function.

G protein-coupled receptors↗