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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

A High-Throughput MEMS-Based Differential Scanning Calorimeter for Direct Thermal Characterization of Antibodies

Calorimeters, which can be used for rapid thermal characterization of biomolecules, are getting intense attention in drug development. This paper presents a novel MEMS-based differential scanning calorimeter (DSC) for direct thermal characterization of protein samples. The DSC consisted of a pair of temperature sensors made by vanadium oxide (VOx) film with a temperature coefficient of resistivity of –0.025/K at 300 K, a microfluidic device with high thermal insulation (2.8 K/mW), and a Peltier heater for linear temperature scanning. The DSC exhibited high sensitivity (6.1 µV/µW), low noise (0.4 µW), high scanning rate (45 K/min), and low sample consumption volume (0.63 µL). The MEMS DSC was verified by measuring the temperature-induced denaturation of lysozyme at different pH, and then used to study the thermal stability of a monoclonal antibody (mAb), an antigen-binding fragment (Fab), and a dual variable domain immunoglobulin (DVD-Ig) at pH = 6. The results showed that lysozyme is a stable protein in the pH range of 4.0–8.0. The protein stability study revealed that the transition temperatures of the intact Fab fragment, mAb, and DVD proteins were comparable with conformational stability results obtained using conventional commercial DSC. These studies demonstrated that the MEMS DSC is an effective tool for directly understanding the thermal stability of antibodies in a high-throughput and low-cost manner compared to conventional calorimeters.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

The Local Topological Free Energy of the SARS-CoV-2 Spike Protein

The novel coronavirus SARS-CoV-2 infects human cells using a mechanism that involves binding and structural rearrangement of its Spike protein. Understanding protein rearrangement and identifying specific amino acids where mutations affect protein rearrangement has attracted much attention for drug development. In this manuscript, we use a mathematical method to characterize the local topology/geometry of the SARS-CoV-2 Spike protein backbone. Our results show that local conformational changes in the FP, HR1, and CH domains are associated with global conformational changes in the RBD domain. The SARS-CoV-2 variants analyzed in this manuscript (alpha, beta, gamma, delta Mink, G614, N501) show differences in the local conformations of the FP, HR1, and CH domains as well. Finally, most mutations of concern are either in or in the vicinity of high local topological free energy conformations, suggesting that high local topological free energy conformations could be targets for mutations with significant impact of protein function. Namely, the residues 484, 570, 614, 796, and 969, which are present in variants of concern and are targeted as important in protein function, are predicted as such from our model.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

A Review of Rattlesnake Venoms

Venom components are invaluable in biomedical research owing to their specificity and potency. Many of these components exist in two genera of rattlesnakes, Crotalus and Sistrurus, with high toxicity and proteolytic activity variation. This review focuses on venom components within rattlesnakes, and offers a comparison and itemized list of factors dictating venom composition, as well as presenting their known characteristics, activities, and significant applications in biosciences. There are 64 families and subfamilies of proteins present in Crotalus and Sistrurus venom. Snake venom serine proteases (SVSP), snake venom metalloproteases (SVMP), and phospholipases A2 (PLA2) are the standard components in Crotalus and Sistrurus venom. Through this review, we highlight gaps in the knowledge of rattlesnake venom; there needs to be more information on the venom composition of three Crotalus species and one Sistrurus subspecies. We discuss the activity and importance of both major and minor components in biomedical research and drug development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Cryogenic X-ray crystallographic studies of biomacromolecules at Turkish Light Source " Turkish DeLight "

X-ray crystallography is a robust and powerful structural biology technique that provides high-resolution atomic structures of biomacromolecules. Scientists use this technique to unravel mechanistic and structural details of biological macromolecules (e.g., proteins, nucleic acids, protein complexes, protein-nucleic acid complexes, or large biological compartments). Since its inception, single-crystal cryocrystallography has never been performed in Türkiye due to the lack of a single-crystal X-ray diffractometer. The X-ray diffraction facility recently established at the University of Health Sciences, Istanbul, Türkiye will enable Turkish and international researchers to easily perform high-resolution structural analysis of biomacromolecules from single crystals. Here, we describe the technical and practical outlook of a state-of-the-art home-source X-ray, using lysozyme as a model protein. The methods and practice described in this article can be applied to any biological sample for structural studies. Therefore, this article will be a valuable practical guide from sample preparation to data analysis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

β-Lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of β-lactamases among pathogenic bacteria limits the efficacy of β-lactam antibiotics. This has created a major public health crisis. The use of β-lactamase inhibitors has proven useful in restoring the activity of β-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-β-lactamases are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia , is a significant contributor to the β-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, α3-β7 and β12-α5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics simulations were performed, Markov State Models were built, and convolutional variational autoencoder-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, and R236) were mutated and the activity of the generated L1 variants was evaluated in cell-based experiments. The results demonstrate that there are extremely significant gating interactions between α3-β7 and β12-α5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1998

Pharmacy in Space: A Session on NASA Technologies

In 1993, Vice-president Gore was charged with creation of a correctional plan for the poor findings from an efficiency study of governmental agencies. That correctional analysis was then used to support efforts to balance the budget in ways anticipated to improve the value returned per tax payer dollar spent. The final result was a broad initiative collectively termed "reinventing the government", which included major restructuring within NASA as well, termed "reinventing NASA This included substantial elimination of middle management and downsizing such that about 2 million government workers employed in 1992 has shrunk now to about 1.2 million government workers who are employed in ways that at least somewhat decrease bureaucratic and programmatic inefficiencies. Today, "reinvented NASA" has an awareness of contractual commitment to the public. NASA now operates within a so-called "strategic plan" that requires awareness and response to domestic needs. This is important to this audience because it means that NASA is committed to exploring interactions that you may wish to initiate. That is, you are urged to explore with NASA on topics of educational support, collaborative research, or commercial partnerships in drug development and application, as the pertinent examples here, in ways that can include involvement of central NASA resources and missions.

Richmond, Robert C.↗
NASA NTRS2008

Producing Newborn Synchronous Mammalian Cells

A method and bioreactor for the continuous production of synchronous (same age) population of mammalian cells have been invented. The invention involves the attachment and growth of cells on an adhesive-coated porous membrane immersed in a perfused liquid culture medium in a microgravity analog bioreactor. When cells attach to the surface divide, newborn cells are released into the flowing culture medium. The released cells, consisting of a uniform population of synchronous cells are then collected from the effluent culture medium. This invention could be of interest to researchers investigating the effects of the geneotoxic effects of the space environment (microgravity, radiation, chemicals, gases) and to pharmaceutical and biotechnology companies involved in research on aging and cancer, and in new drug development and testing.

Gonda, Steve R.↗
NASA NTRS2017

The Research Plan: Closing the ExMC Med02 "Pharmacy" Gap

HRP Human Research Roadmap: Risk and Gap Risk of Adverse Health Outcomes and Decrements in Performance due to Inflight Medical Conditions. Med02 "Pharmacy" Gap: We do not have the capability to provide a safe and effective medication formulary for exploration missions delivering a recommendation for a chemically stable, safe, and effective medication formulary that will support the operational needs of exploration space missions research strategy evidence-based formulary and models innovative analytical tools and methodologies novel treatments and preventive measures Planned review by a panel of experts from the pharmaceutical industry, regulatory, and academic scientific communities Formulary Selection Formulary Potency and Shelf life Formulary Safety and Toxicity Novel Technology Proof-of-Concept Portable real-time chemical analysis Innovative drug development / design

Daniels, Vernie↗
DOE OSTI2021

Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Graph-based featurization methods for classifying small molecule compounds

For over a decade, drug-induced liver injury (DILI) has posed significant drawbacks in the synthesis and development of drugs and remains a consequential concern. With finite success within the existing preclinical models, DILI is one of the main causes of drug withdrawal or termination from the market. Particularly, this withdrawal occurs during the late stages of drug development (Kullak-Ublick, 2017). Since DILI is difficult to diagnose and treat, it has become an obstacle in the drug production market that in turn affects clinicians, pharmaceutical companies, and consumers. We propose a method for learning features of DILI-positive drugs based on the graphical relationships and patterns they possess within a network of biological databases. We also train various statistical and machine learning models on these learned features in order to classify the drugs as DILI-positive or negative. Our methods include Random Forest, Neural networks, and logistic regression classification. We utilize labeled DILI-positive and DILI-negative datasets, which were developed by the FDA and the National center for toxicological research, as well as additional literature datasets (Thakkar, 2020) in order to validate our results and assess our featurization and model accuracy.

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

Fragment-based drug nanoaggregation reveals drivers of self-assembly

Drug nanoaggregates are particles that can deleteriously cause false positive results during drug screening efforts, but alternatively, they may be used to improve pharmacokinetics when developed for drug delivery purposes. The structural features of molecules that drive nanoaggregate formation remain elusive, however, and the prediction of intracellular aggregation and rational design of nanoaggregate-based carriers are still challenging. We investigate nanoaggregate self-assembly mechanisms using small molecule fragments to identify the critical molecular forces that contribute to self-assembly. We find that aromatic groups and hydrogen bond acceptors/donors are essential for nanoaggregate formation, suggesting that both π-π stacking and hydrogen bonding are drivers of nanoaggregation. We apply structure-assembly-relationship analysis to the drug sorafenib and discover that nanoaggregate formation can be predicted entirely using drug fragment substructures. We also find that drug nanoaggregates are stabilized in an amorphous core-shell structure. These findings demonstrate that rational design can address intracellular aggregation and pharmacologic/delivery challenges in conventional and fragment-based drug development processes.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2020

Supercomputing Pipelines Search for Therapeutics Against COVID-19

The urgent search for drugs to combat SARS-CoV-2 has included the use of supercomputers. The use of general-purpose graphical processing units (GPUs), massive parallelism, and new software for high-performance computing (HPC) has allowed researchers to search the vast chemical space of potential drugs faster than ever before. We developed a new drug discovery pipeline using the Summit supercomputer at Oak Ridge National Laboratory to help pioneer this effort, with new platforms that incorporate GPU-accelerated simulation and allow for the virtual screening of billions of potential drug compounds in days compared to weeks or months for their ability to inhibit SARS-COV-2 proteins. Here, this effort will accelerate the process of developing drugs to combat the current COVID-19 pandemic and other diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

The development of SARS-CoV-2 main protease (M pro ) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M pro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M pro . An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M pro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M pro with low nanomolar K i values. Furthermore, these compounds demonstrate efficacy against mutant forms of M pro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50–500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2– 8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Impact of structural biology and the protein data bank on us fda new drug approvals of low molecular weight antineoplastic agents 2019–2023

Abstract Open access to three-dimensional atomic-level biostructure information from the Protein Data Bank (PDB) facilitated discovery/development of 100% of the 34 new low molecular weight, protein-targeted, antineoplastic agents approved by the US FDA 2019–2023. Analyses of PDB holdings, the scientific literature, and related documents for each drug-target combination revealed that the impact of structural biologists and public-domain 3D biostructure data was broad and substantial, ranging from understanding target biology (100% of all drug targets), to identifying a given target as likely druggable (100% of all targets), to structure-guided drug discovery (>80% of all new small-molecule drugs, made up of 50% confirmed and >30% probable cases). In addition to aggregate impact assessments, illustrative case studies are presented for six first-in-class small-molecule anti-cancer drugs, including a selective inhibitor of nuclear export targeting Exportin 1 (selinexor, Xpovio), an ATP-competitive CSF-1R receptor tyrosine kinase inhibitor (pexidartinib,Turalia), a non-ATP-competitive inhibitor of the BCR-Abl fusion protein targeting the myristoyl binding pocket within the kinase catalytic domain of Abl (asciminib, Scemblix), a covalently-acting G12C KRAS inhibitor (sotorasib, Lumakras or Lumykras), an EZH2 methyltransferase inhibitor (tazemostat, Tazverik), and an agent targeting the basic-Helix-Loop-Helix transcription factor HIF-2α (belzutifan, Welireg).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Rational approach to drug discovery for human schistosomiasis

Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma, praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes.

59 BASIC BIOLOGICAL SCIENCES↗