Selected Grantee Publications
- Clear All
- 7 results found
- nigms
- Vaccines/Therapeutics
- 2023
Broad Receptor Tropism and Immunogenicity of a Clade 3 Sarbecovirus
Lee et al., Cell Host and Microbe. 2023.
https://www.sciencedirect.com/science/article/pii/S1931312823004225
Investigators showed that the S glycoprotein of the clade 3 sarbecovirus PRD-0038 in the African Rhinolophus bat has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. They generated a cryogenic electron microscopy structure of the RBD bound to ACE2, explaining receptor tropism and highlighting differences between SARS-CoV-1 and SARS-CoV-2. PRD‑0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses, compared with SARS-CoV-2. These findings underline a potential molecular pathway for zoonotic spillover of a clade 3 sarbecovirus, as well as the need to develop pan-sarbecovirus vaccines and countermeasures. Supported by ORIP (S10OD032290, S10OD026959, S10OD021644), NIAID, NCI, and NIGMS.
A Gut-Restricted Glutamate Carboxypeptidase II Inhibitor Reduces Monocytic Inflammation and Improves Preclinical Colitis
Peters et al., Science Translational Medicine. 2023.
https://www.science.org/doi/10.1126/scitranslmed.abn7491
Many patients with moderate-to-severe inflammatory bowel disease (IBD) do not have adequate disease control, and glutamate carboxypeptidase II (GCPII) offers a promising target for therapeutic development. Researchers generated a class of GCPII inhibitors. They demonstrated that the inhibitor reduced monocytic inflammation in mice and protected against the loss of barrier integrity in primary human colon epithelial air–liquid interface monolayers. Their findings suggest that local inhibition of GCPII could be applied for the development of IBD therapeutics. Supported by ORIP (K01OD030517, T32OD011089), NIGMS, and NCCIH.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
Structural Insights Into the Broad Protection Against H1 Influenza Viruses by a Computationally Optimized Hemagglutinin Vaccine
Dzimianski et al., Communications Biology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37185989/
Influenza is an ongoing public health concern, and computationally optimized broadly reactive antigen (COBRA) hemagglutinin proteins represent a potential strategy for formulating broadly effective influenza vaccines. Researchers determined the crystal structure of COBRA P1, as well as its binding to 1F8, a broadly neutralizing antibody. This work provides valuable insights into the underlying molecular basis for the broad effectiveness of P1, and these insights can be applied to future vaccine designs. Supported by ORIP (K01OD026569), NIAID, and NIGMS.
Anti–Human Immunodeficiency Virus‑1 Activity of MoMo30 Protein Isolated from the Traditional African Medicinal Plant Momordica balsamina
Khan et al., Virology Journal. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035133/
Momordica balsamina has been reported to produce a ribosome-inactivating protein with anti‑HIV-1 activity and is commonly used by traditional African healers for treatment of HIV. Investigators characterized the mechanism of action of the MoMo30 protein, as well as the sequence of the protein-coding gene. They reported that MoMo30 functions as a lectin or carbohydrate-binding agent (CBA) and inhibits HIV-1 at nanomolar levels, with minimal cellular toxicity at inhibitory levels. CBAs can block the binding of envelope glycoproteins with their target receptors on cells. Thus, this protein could represent a potential new treatment strategy for HIV. Supported by ORIP (R24OD010947), NCI, NIGMS, and NIMHD.
Mechanism of STMN2 Cryptic Splice-Polyadenylation and its Correction for TDP-43 Proteinopathies
Baughn et al., Science. 2023.
Loss of the RNA-binding protein TDP-43 from the nuclei of affected neurons is a hallmark of neurodegeneration in TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia). Loss of functional TDP-43 is accompanied by misprocessing of the stathmin-2 (STMN2) RNA precursor. Investigators determined the elements through which TDP‑43 regulates STMN2 pre‑mRNA processing and identified steric binding antisense oligonucleotides that are capable of restoring normal STMN2 protein and RNA levels. This approach is potentially applicable for human therapy. Supported by ORIP (U42OD010921), NIA, NCI, NIGMS, and NINDS.