A5070830007- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Click Chemistry and Applications
- Tuberculosis Research and Epidemiology
- Pneumocystis jirovecii pneumonia detection and treatment
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Antibiotics Pharmacokinetics and Efficacy
- RNA and protein synthesis mechanisms
- Infectious Diseases and Tuberculosis
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Drug-Induced Hepatotoxicity and Protection
- Antibiotic Resistance in Bacteria
- DNA Repair Mechanisms
- Nuclear Structure and Function
- Mycobacterium research and diagnosis
- Microscopic Colitis
- Cancer therapeutics and mechanisms
- Orthopedic Infections and Treatments
- Clostridium difficile and Clostridium perfringens research
- PARP inhibition in cancer therapy
- Neurotransmitter Receptor Influence on Behavior
Carisma Therapeutics (United States)
2025
Rutgers, The State University of New Jersey
2017-2020
Rutgers New Jersey Medical School
2017-2020
Drexel University
2008-2016
Harvard University
2008
Bryn Mawr College
2008
Institute for Molecular Medicine
2008
Dana-Farber Cancer Institute
2008
Dickinson College
2007
The homologous recombination (HR) pathway plays a crucial role in the repair of DNA double-strand breaks (DSBs) and interstrand cross-links (ICLs). RAD51, key protein HR, possesses unique activity: strand exchange between sequences. Recently, using high-throughput screening (HTS), we identified compound 1 (B02), which specifically inhibits activity human RAD51. Here, analyzed mechanism inhibition found that disrupts RAD51 binding to DNA. We then examined effect on HR cell. results show...
ABSTRACT The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential interact N-terminal domain (NTD) CA disrupt early, preintegration steps cycle. molecule 4,4′-[dibenzo[ b,d ]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity single- multiple-round infections but...
Abstract Indian rhesus macaques (Macaca mulatta) are routinely used in preclinical studies to evaluate therapeutic Abs and candidate vaccines. The efficacy of these interventions many cases is known rely heavily on the ability interact with a set Ab FcγR expressed innate immune cells. Yet, despite their presumed functional importance, M. mulatta receptors largely uncharacterized, posing fundamental limit ensuring accurate interpretation translation results from this model. In article, we...
Abstract The development of drug resistance remains a critical problem for current HIV‐1 antiviral therapies, creating need new inhibitors replication. We previously reported on novel anti‐HIV‐1 compound, N 2 ‐(phenoxyacetyl)‐ ‐[4‐(1‐piperidinylcarbonyl)benzyl]glycinamide ( 14 ), that binds to the highly conserved phosphatidylinositol (4,5)‐bisphosphate (PI(4,5)P ) binding pocket matrix (MA) protein. In this study, we re‐evaluate hits from virtual screen used identify compound and test them...
Many large natural product antibiotics act by specifically binding and sequestering target molecules found on bacterial cells. We have developed a new strategy to expedite the structural analysis of such antibiotic-target complexes, in which we covalently link carrier proteins, then crystallize entire carrier-target-antibiotic complex. Using native chemical ligation, linked Lys-D-Ala-D-Ala epitope for glycopeptide three different proteins. show that recognition this peptide multiple is not...
Structure–activity correlations were investigated for substituted peptide conjugates that function as dual receptor site antagonists of HIV-1 gp120. A series constructed via click reaction both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from the parent 1 (12p1, RINNIPWSEAMM). Compared to 1, many these found exhibit several orders magnitude increase in affinity gp120 inhibition potencies at CD4 coreceptor binding sites We sought determine structural...
Abstract In this work, we identified a high affinity and potency metallocene‐containing triazole peptide conjugate that suppresses the interactions of HIV‐1 envelope gp120 at both its CD4 co‐receptor binding sites. The ferrocene‐peptide conjugate, HNG‐156, was formed by an on‐resin copper‐catalysed [2 + 3] cycloaddition reaction. Surface plasmon resonance interaction analysis revealed that, compared to previously reported phenyl‐containing HNG‐105 ( 105 ), 156 had higher direct for several...
Abstract In an effort to identify broadly active inhibitors of HIV‐1 entry into host cells, we previously reported a family dodecamer triazole–peptide conjugates with nanomolar affinity for the viral surface protein gp120. This peptide class exhibits potent antiviral activity and capacity simultaneously inhibit interaction envelope both CD4 co‐receptor. this investigation, minimized structural complexity lead triazole inhibitor HNG‐156 (peptide 1 ) explore limits pharmacophore that enables...
ABSTRACT Clostridium difficile -associated disease (CDAD) constitutes a large majority of nosocomial diarrhea cases in industrialized nations and is mediated by the effects two secreted toxins, toxin A (TcdA) B (TcdB). Patients who develop strong antitoxin antibody responses can clear C. infection remain free. Key toxin-neutralizing epitopes have been found within carboxy-terminal receptor binding domains (RBDs) TcdA TcdB, which has generated interest developing RBD as viable vaccine target....
Multidrug-resistant bacterial infections are commonly treated with glycopeptide antibiotics such as teicoplanin. This drug inhibits cell-wall biosynthesis by binding and sequestering a precursor: d-alanine-containing peptide. A carrier-protein strategy was used to crystallize the complex of teicoplanin its target peptide fusing either MBP or ubiquitin via native chemical ligation subsequently crystallizing protein–peptide–antibiotic complex. The 2.05 Å resolution MBP–peptide–teicoplanin...
Individual pharmacokinetic variability is a driver of poor tuberculosis (TB) treatment outcomes. We developed method for measurement rifampin concentrations by urine colorimetry and mobile phone photographic application to predict clinically important serum measurements in children treated TB.
Despite advances in HIV therapy, viral resistance and side-effects with current drug regimens require targeting new components of the virus. Dual antagonist peptide triazoles (PT) are a novel class HIV-1 inhibitors that specifically target gp120 component spike inhibit its interaction both cell surface protein ligands, namely initial receptor CD4 co-receptor (CCR5/CXCR4), thus preventing entry. Following an survey 19 alanine mutants by ELISA, we screened 11 for their importance binding to,...
Pyrazinamide is a key drug in the first-line treatment regimen for tuberculosis, with potent sterilizing effect. Although low pyrazinamide peak serum concentrations (Cmax) are associated poor outcomes, many resource-constrained settings do not have sufficient laboratory capacity to support therapeutic monitoring (TDM). The objective of this study was determine whether colorimetric test urine can identify tuberculosis patients adequate exposures, as defined by Cmax above target threshold.In...
The cost and complexity of current approaches to therapeutic drug monitoring during tuberculosis (TB) therapy limits widespread use in areas greatest need. We sought determine whether urine colorimetry could have a novel application as form anti-TB therapy. Among healthy volunteers, we evaluated 3 dose sizes rifampin (150 mg, 300 600 mg), performed intensive pharmacokinetic sampling, collected timed void at 4 h post-dosing. absorbance peak 475 nm was measured after rifamycin extraction....
There is considerable uncertainty regarding the optimal use of rifampicin for treatment tuberculous (TB) meningitis. A pharmacokinetic modeling and simulation study concentrations in cerebrospinal fluid (CSF) during TB meningitis was performed this study.Parameters pharmacokinetics CSF were estimated using individual-level data, model externally validated three separate patient cohorts. Monte Carlo simulations serum performed. The area under concentration-versus-time curve 24 h (AUC0-24)...
We investigated the interaction between cross-reactive HIV-1 neutralizing human monoclonal antibody m18 and HIV-1YU-2 gp120 in an effort to understand how this inhibits entry of virus into cells. binds with high affinity (KD≈5 nM) as measured by surface plasmon resonance (SPR) isothermal titration calorimetry (ITC). SPR analysis further showed that interactions both soluble CD4 CD4-induced antibodies have epitopes overlapping coreceptor binding site. This dual receptor site antagonism, which...
Background: The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related cellular oxidation/reduction status downstream markers oxidative DNA damage. Methods: performed intensive sampling among isoniazid-treated patients the relative plasma isoniazid, acetylisoniazid, hydrazine, acetylhydrazine....
In the absence of universally available antiretroviral (ARV) drugs or a vaccine against HIV-1, microbicides may offer most immediate hope for controlling AIDS pandemic. The advanced and clinically effective are based on ARV agents that interfere with earliest stages HIV-1 replication. Our objective was to identify characterize novel ARV-like inhibitors, as well demonstrate their efficacy at blocking transmission. Abasic phosphorothioate 2' deoxyribose backbone (PDB) oligomers were evaluated...
Background . Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, rifampin pharmacokinetic parameters a pilot study 6 HIV-infected, tuberculosis-uninfected who were naïve antiretroviral therapy....
ABSTRACT Background The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related cellular oxidation/reduction status downstream markers oxidative DNA damage. Methods performed intensive sampling among isoniazid-treated patients the relative plasma isoniazid, acetylisoniazid, hydrazine, acetylhydrazine....