COVID-19 Drug Discovery Dataset
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Kim, Hyojin↗
SEARCH · Engineering Papers
Results for “therapeutic design”
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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Considerations for Medical Transport from the Space Station via an Assured Crew Return Vehicle (ACRV)
In developing a permanently crewed space station, the importance of medical care has been continually reaffirmed; and the health maintenance facility (HMF) is an integral component. It has diagnostic, therapeutic, monitoring, and information management capability. It is designed to allow supportive care for: (1) non-life-threatening illnesses; e.g., headache, lacerations; (2) moderate to severe, possibly life-threatening illnesses; e.g., appendicitis, kidney stones; and (3) severe, incapacitating, life-threatening illnesses; e.g., major trauma, toxic exposure. Since the HMF will not have a general surgical capability, the need for emergency escape and recovery methods has been studied. Medical risk assessments have determined that it is impossible to accurately predict the incidence of crewmember illness/injury. A best estimate is 1:3 per work-year, with 1% of these needing an ACRV. For an eight-person crew, this means that one assured crew return vehicle (ACRV) will be used every 4 to 12 years. The ACRV would serve at least three basic objectives as: (1) a crew return if the space shuttle is unavailable; (2) an escape vehicle from a major time-critical space station emergency; and (3) a full or partial crew return vehicle for a medical emergency. The focus of this paper is the third objective for the ACRV.
Stepaniak, Philip↗
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↗
Human Monoclonal IgE Antibodies—a Major Milestone in Allergy
This review provides an overview of this major milestone in allergy, the first atomic resolution structure of an authentic human IgE epitope. The molecular insights that IgE epitopes provide will allow for structure-based design approaches to the development of novel diagnostics, antibody therapeutics, and immunotherapies.
59 BASIC BIOLOGICAL SCIENCES↗
An elastin-like polymer targeting vascular endothelial growth factor receptor-1 reduces survival in serum-starved endothelial cells
Peptides often exhibit biological activity that depends on the context in which they are displayed and delivered. Understanding and controlling these contextual effects on peptide function is critical for designing targeted and responsive peptide-based biomaterials and therapeutics. Genetically engineered protein polymers such as elastin-like polypeptides (ELPs) can incorporate bioactive peptide motifs and are attractive candidates for biomaterials used in tissue engineering and targeted drug delivery. They also present an opportunity for investigating and modulating cell signaling pathways by presenting a peptide ligand in various defined chemical and physical environments. Vascular endothelial growth factor receptor-1 (VEGFR1) signaling plays important and complex roles in cell survival and angiogenesis, but polymeric materials that interact with this signaling axis are scarce. In this study, a novel genetically engineered elastin-like polymer that targets VEGFR1 is characterized. This polymer, termed R1B-ELP, binds to human endothelial cells in a manner dependent on its VEGFR1-targeting motif and, based on cell proliferation and cytotoxicity assays, demonstrates activity consistent with disrupting pro-survival signaling necessary for endothelial cell function under conditions of environmental stress. Notably, these findings indicate that ELP fusion alters the functional behavior of the targeting peptide. Modulators of VEGFR1 signaling have potential applications in basic studies of angiogenesis as well as in therapeutic applications targeting vascular or inflammatory diseases.
36 MATERIALS SCIENCE↗
Spectral decomposition of human BCL2 bonded to a PROTAC
In this study, we have decomposed the linear infrared spectra and two-dimensional infrared spectroscopy of a VHL-recruiting Proteolysis-targeting chimera (PROTAC) complex with BCL-2 to understand the spectral signatures of this complex. Our findings show that both VHL and BCL-2 units have distinct spectral signatures that contribute to the total spectra in different regions. Furthermore, we observed that the interaction between VHL and BCL-2 within the PROTAC complex leads to unique spectral features, indicating a strong synergistic effect. Through detailed analysis, specific bands were identified that correspond to the vibrational modes of the individual components, as well as their interactive modes within the complex. This study provides valuable insight into the molecular interactions within the PROTAC complex, offering a deeper understanding of its structure and function. These insights could be pivotal in designing more efficient PROTACs for targeted protein degradation in therapeutic applications.
Nauta, Wiestke [University of Groningen]↗
Deep Active Learning based Experimental Design
This project is an implementation of the Deep Active Learning (DeepAL) framework from the paper Deep Active Learning based Experimental Design to Uncover Synergistic Genetic Interactions for Host Targeted Therapeutics
Zhu, Haonan [Lawrence Livermore National Laborator↗
Production of ent-kaurene from lignocellulosic hydrolysate in Rhodosporidium toruloides
Abstract Background Rhodosporidium toruloides has emerged as a promising host for the production of bioproducts from lignocellulose, in part due to its ability to grow on lignocellulosic feedstocks, tolerate growth inhibitors, and co-utilize sugars and lignin-derived monomers. Ent -kaurene derivatives have a diverse range of potential applications from therapeutics to novel resin-based materials. Results The Design, Build, Test, and Learn (DBTL) approach was employed to engineer production of the non-native diterpene ent -kaurene in R. toruloides . Following expression of kaurene synthase (KS) in R. toruloides in the first DBTL cycle, a key limitation appeared to be the availability of the diterpene precursor, geranylgeranyl diphosphate (GGPP). Further DBTL cycles were carried out to select an optimal GGPP synthase and to balance its expression with KS, requiring two of the strongest promoters in R. toruloides , ANT (adenine nucleotide translocase) and TEF1 (translational elongation factor 1) to drive expression of the KS from Gibberella fujikuroi and a mutant version of an FPP synthase from Gallus gallus that produces GGPP. Scale-up of cultivation in a 2 L bioreactor using a corn stover hydrolysate resulted in an ent -kaurene titer of 1.4 g/L. Conclusion This study builds upon previous work demonstrating the potential of R. toruloides as a robust and versatile host for the production of both mono- and sesquiterpenes, and is the first demonstration of the production of a non-native diterpene in this organism.
59 BASIC BIOLOGICAL SCIENCES↗
Structure-Based Design of Small-Molecule Inhibitors of Human Interleukin-6
Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. As a critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high-throughput structure-based computational screening using ensemble docking for small-molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scoring ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with the second-highest calculated binding affinity experimentally showed an ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 μM concentration. This finding may pave the way for designing small-molecule inhibitors of hIL-6 of therapeutic significance.
Human Interleukin-6↗
Human Spaceflight Applications of Novel Miniature X-Ray Technologies
INTRODUCTION: Radiography (XR) has long been a cornerstone of terrestrial medical imaging, though it has not yet been used in the spaceflight environment. Medical systems for human spaceflight missions are constrained by mass, volume, and power, and until recently, XR systems have been considered too large and power-consuming for spaceflight diagnostic and therapeutic applications. However, the rise of commercial spaceflight and NASA’s refocused efforts on returning crews to the Moon for long-duration missions have introduced a higher degree of medical risk to human spaceflight and require a re-evaluation when optimizing medical system design. Over the last decade, XR devices have miniaturized while maintaining good diagnostic and therapeutic sensitivity and specificity, making new in-flight medical and non-medical XR applications a possibility. Initial research identified several medical conditions where miniature XR would be beneficial for the diagnosis and/or management of medical conditions arising in space, though a more in-depth analysis is required to identify whether XR may add value to the management of such conditions. With this presentation, we aim to introduce the potential utility of miniature XR, review prior work highlighting where XR may be beneficial, and evaluate how miniature XR may reduce medical risk in human spaceflight missions. METHODS: IMPACT (Informing Mission Planning via Analysis of Complex Tradespaces) is a risk assessment tool developed by NASA to advance exploration mission medical system design by quantitatively estimating mission medical risk. IMPACT v1.0 includes a novel evidence library baselined to exploration environments, an expanded list of 119 medical conditions, medical capabilities and resources critical for management of these medical conditions, and the ability for rapid and iterative analysis in the setting of modifiable design reference missions (DRMs). Our first analysis identified which of the 119 medical conditions XR had diagnostic or therapeutic utility for. Subject matter experts (SMEs) recorded which XR views would be performed under ideal terrestrial circumstances for diagnosis/management of each condition, as well as which views are pragmatic for spaceflight limitations. A second analysis utilized IMPACT to identify significant conditions that contribute greatest to medical risk during a notional long-duration Lunar orbit and Lunar surface DRM. Medical system risk estimates include loss of crew life (LOCL), need for return to definitive care (RTDC; medical evacuation), and an estimate of crew task time affected (TTA). Using a standardized semi-quantitative scoring methodology, a deeper evaluation of each of the most significant medical conditions was performed. Data from both of these separate analyses were used to hypothesize what ideal and pragmatic XR studies may impact clinical management of the most significant conditions predicted to lead to medical risk. RESULTS: Approximately 1/3 of the IMPACT conditions were identified as being more effectively or comprehensively assessed or treated with the addition of miniature XR technology. The resulting conditions benefitting diagnostically and therapeutically from XR are revealed, as well as the ideal and pragmatic XR views and medical procedures benefitting from XR. The conditions of clinical significance and those most contributing to risk are also displayed. Among the conditions that contribute greatest to LOCL, four conditions for which XR may improve the diagnosis and management of include: decompression sickness, traumatic shock, dental abscess, and respiratory failure. Among conditions that contributed to RTDC, the evaluation and management of wrist fracture is likely improved by XR. For conditions leading to crew TTA, evaluation and management of EVA shoulder injuries, upper and lower extremity strains, back strains, and EVA hand injuries are likely improved by XR. DISCUSSION: Miniature XR in spaceflight has the potential to improve the evaluation and management of a substantial portion of conditions that most contribute to medical risk. This presentation is an introduction to the possibilities miniature XR provides for future human spaceflight missions and subsequent presenters will expand on potential applications in more detail. LEARNING OBJECTIVES: 1) Understand the previous limitations of using radiography in the management of spaceflight medical conditions; 2) Evaluate the findings from the IMPACT tool analysis, which allows quantification of the benefit miniature XR could provide for managing high-risk medical conditions in long-duration lunar orbit and surface missions, focusing on improvements in crew health outcomes; 3) Analyze case studies where miniature XR technology could reduce the medical risks associated with spaceflight missions, specifically in diagnosing and managing conditions such as decompression sickness, traumatic shock, and EVA-related injuries.
A Anderson↗
De novo design of D-peptide ligands: Application to influenza virus hemagglutinin
D-peptides hold great promise as therapeutics by alleviating the challenges of metabolic stability and immunogenicity in L-peptides. However, current D-peptide discovery methods are severely limited by specific size, structure, and the chemical synthesizability of their protein targets. Here, we describe a computational method for de novo design of D-peptides that bind to an epitope of interest on the target protein using Rosetta’s hotspot-centric approach. The approach comprises identifying hotspot sidechains in a functional protein–protein interaction and grafting these side chains onto much smaller structured peptide scaffolds of opposite chirality. The approach enables more facile design of D-peptides and its applicability is demonstrated by design of D-peptidic binders of influenza A virus hemagglutinin, resulting in identification of multiple D-peptide lead series. The X-ray structure of one of the leads at 2.38 Å resolution verifies the validity of the approach. This method should be generally applicable to targets with detailed structural information, independent of molecular size, and accelerate development of stable, peptide-based therapeutics.
Science & Technology - Other Topics↗
Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment
Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.
59 BASIC BIOLOGICAL SCIENCES↗
LIFT Tenant Is Off and Running
Lewis Incubator for Technology (LIFT) tenant, Analiza Inc., graduated from the incubator July 2000. Analiza develops technology and products for the early diagnosis of diseases, quality control of bio-pharmaceutical therapeutics, and other applications involving protein analyses. Technology links with NASA from existing and planned work are in areas of microfluidics and laser light scattering. Since their entry in LIFT in May, 1997, Analiza has: Received a $750,000 grant from the National Institutes of Health. Collaborated with a Nobel Prize winner on drug design. Collaborated with Bristol-Myers Squibb on the characterization of biological therapeutics. Added a Ph.D. senior scientist and several technicians. Received significant interest from major pharmaceutical companies about collaborating and acquiring Analiza technology.
Steele, Gynelle C.↗
Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering
The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) “killer domains” of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs.
59 BASIC BIOLOGICAL SCIENCES↗
Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib
Bruton’s tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.
60 APPLIED LIFE SCIENCES↗
Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives
Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source “Turkish DeLight” to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors.
60 APPLIED LIFE SCIENCES↗
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↗
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↗