A5045390563- Immune Response and Inflammation
- Antimicrobial Peptides and Activities
- Immunotherapy and Immune Responses
- Influenza Virus Research Studies
- RNA Interference and Gene Delivery
- Immune Cell Function and Interaction
- SARS-CoV-2 and COVID-19 Research
- Pneumonia and Respiratory Infections
- Lipid Membrane Structure and Behavior
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- HIV Research and Treatment
- Pediatric health and respiratory diseases
- Antibiotics Pharmacokinetics and Efficacy
- Synthesis and Biological Evaluation
- Antibiotic Resistance in Bacteria
- NF-κB Signaling Pathways
- Autophagy in Disease and Therapy
- Biopolymer Synthesis and Applications
- Carbohydrate Chemistry and Synthesis
- Antimicrobial agents and applications
- COVID-19 Clinical Research Studies
- Cytokine Signaling Pathways and Interactions
- Cancer therapeutics and mechanisms
- Sepsis Diagnosis and Treatment
- Cancer Treatment and Pharmacology
University of Minnesota
2016-2020
University of Kansas
2007-2016
The University of Tokyo
2014
Shimizu (Japan)
2014
Institute of Medicinal Plant Development
2009-2010
Nanyang Technological University
2007
University Medical Center
2000
University of Kansas Medical Center
1999-2000
Laboratoire de Génétique Cellulaire
2000
Christian Medical College & Hospital
1992-1997
Significance The newest generation of small-molecule vaccine adjuvants aims at triggering specific receptors expressed by dendritic cells, the working horses our immune system. Unfortunately, owing to their small size, upon administration these molecules rapidly enter systemic circulation and cause inflammation. We report on a nanotechnology-based solution for this issue covalent ligation potent immunostimulatory molecule hydrogel nanoparticles. This approach allows lymph node-restricted...
Engagement of toll-like receptors serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary anamnestic responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine A structure−activity study was conducted on the TLR7-agonistic imidazoquinolines, starting 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol a lead. Modifications...
Abstract Localized therapeutic modalities that subvert the tumor microenvironment from immune‐suppressive to pro‐immunogenic can elicit systemic antitumor immune responses induce regression of directly treated as well nontreated distal tumors. A key toward generating robust T cell is activation dendritic cells (DCs) in microenvironment. Treatment with agonists triggering various pattern recognition receptors very efficient activate DCs, yet suffers induction serious immune‐related adverse...
Toll-like receptor 7 (TLR7) is an innate immune for single-stranded RNA (ssRNA) and has important roles in infectious diseases. We previously reported that TLR7 shows synergistic activation response to two ligands, guanosine ssRNA. However, the specific ssRNA sequence preference, detailed recognition mode of its ligand, molecular determinants TLR8 selectivity remain unknown. Here, we report on from a large-scale crystallographic study combined with multifaceted approach. reveal successive...
Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from site injection into systemic circulation. Here, we report on design and synthesis an amphiphilic polymer-prodrug conjugate imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures 200 nm. The contains endosomal enzyme-responsive linker enabling degradation...
Abstract The search for vaccines that protect from severe morbidity and mortality because of infection with acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus causes disease 2019 (COVID‐19) is a race against clock virus. Here we describe an amphiphilic imidazoquinoline (IMDQ‐PEG‐CHOL) TLR7/8 adjuvant, consisting conjugated to chain end cholesterol‐poly(ethylene glycol) macromolecular amphiphile. It water‐soluble exhibits massive translocation lymph nodes upon local...
A “universal” platform that can rapidly generate multiplex vaccine candidates is critically needed to control pandemics. Using the severe acute respiratory syndrome coronavirus 2 as a model, we have developed such by CRISPR engineering of bacteriophage T4. pipeline was engineered incorporating various viral components into appropriate compartments phage nanoparticle structure. These include expressible spike genes in genome, and envelope epitopes surface decorations, nucleocapsid proteins...
The generation of specific humoral and cellular immune responses plays a pivotal role in the development effective vaccines against tumors. Especially presence antigen-specific, cytotoxic T cells influences outcome therapeutic cancer vaccinations. Different strategies, ranging from delivering antigen-encoding mRNAs to peptides or full antigens, are accessible but often suffer insufficient immunogenicity require immune-boosting adjuvants as well carrier platforms ensure stability adequate...
Abstract Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop (TB) after infection, 90% these infections are latent. Further, mice nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit in vitro, suggesting that M1-MΦs may be able regulate anti-TB immunity. We sought determine whether human MΦ heterogeneity contributes TB Here we show IFN-γ-programmed degrade through increased...
Vaccines that target the pre-erythrocytic stage of malaria lifecycle have potential to provide sterilizing immunity but must elicit sustained, high-titer antibody responses completely prevent infection. Most vaccines circumsporozoite protein (CSP), major surface antigen on Plasmodium falciparum sporozoites. Antibodies targeting distinct epitopes within central repeat region CSP protection from infection, we focused developing a highly vulnerable epitope is targeted by potent monoclonal L9....
The first barrier that an antimicrobial agent must overcome when interacting with its target is the microbial cell wall. In case of Gram-negative bacteria, additional to cytoplasmic membrane and peptidoglycan layer, outer (OM) outermost barrier. OM has asymmetric distribution lipids phospholipids lipopolysaccharide (LPS) located in inner leaflets, respectively. contrast, Gram-positive bacteria lack possess a much thicker layer compared their counterparts. An class amphiphiles exists...
In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via Groebke–Blackburn–Bienaymé multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as aldehyde component, furo[2,3-c]pyridines, rather than expected imidazo[1,2-a]pyridines, were obtained, which characterized by NMR spectroscopy crystallography....
Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence selectivity for TLR7 vis-à-vis TLR8 on electronic configurations heterocyclic systems, which we sought examine quantitatively with goal developing "heuristics" define structural requisites governing activity at and/or TLR8. We...
Small molecule immuno-modulators such as agonists of Toll-like receptors (TLRs) are attractive compounds to stimulate innate immune cells toward potent antiviral and antitumor responses. However, small molecules rapidly enter the systemic circulation cause "wasted inflammation". Hence, synthetic strategies confine their radius action lymphoid tissue great relevance, both enhance efficacy concomitantly limit toxicity. Here, we demonstrate that covalent conjugation a TLR7/8 agonist...
Uncontrolled systemic inflammatory immune triggering has hampered the clinical translation of several classes small-molecule immunomodulators, such as imidazoquinoline TLR7/8 agonists for vaccine design and cancer immunotherapy. By taking advantage inherent serum-protein-binding property lipid motifs their tendency to accumulate in lymphoid tissue, we designed amphiphilic lipid-polymer conjugates that suppress inflammation but provoke potent lymph-node activation. This work provides a...
Small-molecular Toll-like receptor 7/8 (TLR7/8) agonists hold promise as immune modulators for a variety of therapeutic purposes including cancer therapy or vaccination. However, due to their rapid systemic distribution causing difficult-to-control inflammatory off-target effects, application is still problematic, in particular systemically. To address this problem, we designed and robustly fabricated pH-responsive nanogels serving versatile immunodrug nanocarriers safe delivery...
The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from activate innate immune responses by engaging Toll-like receptor 2 (TLR2) and highly immunostimulatory yet without apparent toxicity in animal models. lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure−activity relationships such have largely been obtained using murine cells, it is now clear that significant...
Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary anamnestic responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine We synthesized a dendrimeric molecule bearing six units potent TLR7/TLR8 dual-agonistic imidazoquinoline explore if multimerization TLR7/8 would result in altered activity profiles. A complete loss...
Toll-like receptors (TLRs) are pattern recognition that recognize specific molecular patterns present in molecules broadly shared by pathogens but structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result TLR7-antagonistic compounds which may be value addressing innate immune activation-driven exhaustion...
Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines regioisomeric furo[3,2-c]quinolines derived via a tandem, one-pot Sonogashira coupling intramolecular 5-endo-dig cyclization strategy in panel primary screens. observed pure TLR8-agonistic activity profile select...