A5040740420- Alzheimer's disease research and treatments
- Respiratory viral infections research
- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- Cytomegalovirus and herpesvirus research
- Pneumonia and Respiratory Infections
- Herpesvirus Infections and Treatments
- RNA Interference and Gene Delivery
- Viral gastroenteritis research and epidemiology
- Protein Structure and Dynamics
- Animal Virus Infections Studies
- Biochemical and Molecular Research
- Histone Deacetylase Inhibitors Research
- Reproductive tract infections research
- Molecular Biology Techniques and Applications
- RNA and protein synthesis mechanisms
- Cholinesterase and Neurodegenerative Diseases
- Immune Response and Inflammation
- SARS-CoV-2 and COVID-19 Research
- Immunotherapy and Immune Responses
- HIV/AIDS Research and Interventions
- RNA Research and Splicing
- Viral Infections and Immunology Research
- Neonatal Respiratory Health Research
United States Military Academy
2010-2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2023
Merck (Japan)
2019
Merck (Germany)
2017
Temple University
2008
Tufts University
2002
Salk Institute for Biological Studies
1995-1998
Duke University
1989
Integrase is essential for human immunodeficiency virus-type 1 (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity a manner consistent with integration. In this report, we describe diketo acid inhibitors HIV-1 integrase that manifest as consequence their effect on The these compounds due exclusively to one two catalytic functions integrase, strand transfer.
The process of integrating the reverse-transcribed HIV-1 DNA into host chromosomal is catalyzed by virally encoded enzyme integrase (IN). Integration requires two metal-dependent reactions, 3' end processing and strand transfer. Compounds that contain a diketo acid moiety have been shown to selectively inhibit transfer reaction IN in vitro infected cells are effective as inhibitors replication. To characterize molecular basis inhibition, we used functional assays binding evaluate series...
Histone deacetylases (HDACs) act on histones within the nucleosome-bound promoter of human immunodeficiency virus type 1 (HIV-1) to maintain proviral latency. HDAC inhibition leads expression and escape HIV from We evaluated ability potent inhibitor recently licensed for use in oncology, suberoylanilide hydroxamic acid (SAHA; Vorinostat), selective Class I HDACs, induce cell lines production resting CD4(+) T cells antiretroviral-treated, aviremic HIV-infected patients. In J89, a Jurkat line...
The RSV Fusion (F) protein is a target for neutralizing antibody responses and focus vaccine discovery; however, the process of entry requires F to adopt metastable prefusion form transition more stable postfusion form, which displays less potent epitopes. mRNA vaccines encode antigens that are translated by host cells following vaccination, may allow conformational transitions similar those observed during natural infection occur. Here we evaluate panel chemically modified expressing...
The increasing incidence of resistance to current HIV-1 therapy underscores the need develop antiretroviral agents with new mechanisms action. Integrase, one three viral enzymes essential for replication, presents an important yet unexploited opportunity drug development. We describe here identification and characterization L-870,810, a small-molecule inhibitor integrase potent antiviral activity in cell culture good pharmacokinetic properties. L-870,810 is...
Diketo acids such as L-731,988 are potent inhibitors of HIV-1 integrase that inhibit integration and viral replication in cells. These compounds exhibit the unique ability to strand transfer activity absence an effect on 3′ end processing. To understand reasons for this distinct inhibitory profile, we developed a scintillation proximity assay permits analysis radiolabeled inhibitor binding function. High-affinity is shown require assembly specific complex long terminal repeat. The...
We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit production secreted amino terminal fragment an artificial amyloid precursor protein in cell culture. In addition to potent inhibition a cell-based assay (IC50 < 100 nM), these display impressive selectivity against other biologically relevant aspartyl proteases.
Histone deacetylase (HDAC) inhibitors such as valproic acid (VPA) induce the expression of quiescent proviral human immunodeficiency virus type 1 (HIV-1) and may deplete infection in vivo. To uncover novel molecular mechanisms that maintain HIV latency, we sought cellular mRNAs whose was diminished resting CD4(+) T cells HIV-1-infected patients exposed to VPA. c-Myc prominent among genes markedly downregulated upon exposure repressed HIV-1 chronically infected cell lines. Chromatin...
Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4(+) T cells is a significant contributor to persistence infection, allowing evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase (HDAC) inhibitors are capable inducing expression quiescent HIV-1 latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine specific HDACs that regulate transcription, we evaluated HDAC1 HDAC11...
A family of histone deacetylases (HDACs) mediates chromatin remodeling, and repression gene expression. Deacetylation histones within the HIV-1 long terminal repeat (LTR) by HDACs plays a key role in maintenance latency, whereas acetylation about LTR is linked to proviral expression escape HIV from latency. Global HDAC inhibition may adversely affect host expression, leading cellular toxicities. Potent inhibitors selective for that maintain could be ideal antilatency therapeutics.We...
Significance Congenital human cytomegalovirus (HCMV) infection is an important cause of newborn disability, and developing a vaccine against congenital HCMV top priority. However, despite decades efforts, remains elusive. Previous vaccines lacked antigen called pentameric glycoprotein H (gH) complex, essential for the virus to infect epithelial/endothelial cells, these induced poor neutralizing antibodies. To support unique concept featuring gH we established 45 mAbs from rabbit immunized...
Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for RSV infection is highest in infants older adults. A safe effective vaccine adults represents a serious unmet medical need due to higher morbidity mortality this age group. In randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability immunogenicity of an investigational messenger ribonucleic acid...
A new replication-defective human cytomegalovirus vaccine shows promise in protecting against this dangerous virus that can cause severe neurodevelopmental defects babies.
Significance The urgency of curbing the COVID-19 pandemic has motivated many investigators to pivot their research understand basic biology SARS-CoV-2 and search for new pharmaceutical compounds potential treatment. However, most studies require biosafety level 3 facilities, which are in high demand, costly, difficult access. To overcome these limitations, we engineered a replicon, is modified virus subgenome capable self-replicating without producing infectious virus, allowing viral...
Respiratory syncytial virus (RSV) infection is a major cause of respiratory illness in infants and the elderly. Although several vaccines have been developed, none succeeded part due to our incomplete understanding correlates immune protection. While both T cells antibodies play role, emerging data suggest that antibody-mediated mechanisms alone may be sufficient provide Therefore, map humoral immunity against RSV, antibody responses across six different were profiled highly controlled...
β-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of is an essential step in the generation potentially neurotoxic and amyloidogenic Aβ42 peptides Alzheimer9s disease. Although previous mouse studies have shown brain Aβ lowering after BACE1 inhibition, extension such to nonhuman primates or man was precluded by poor potency, penetration, pharmacokinetics available inhibitors. In this study, a novel tertiary carbinamine inhibitor, (TC)-1, assessed unique cisterna magna...
Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized combination of small molecule and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) be targeted selective induction latent HIV-1 expression. Individual depletion HDAC3 significantly induced expression from promoter in 2D10 latency cell line model. However, HDAC1 or −2 alone did...
RNA interference (RNAi) high-throughput screening (HTS) experiments carried out using large (>5000 short interfering [si]RNA) libraries generate a huge amount of data. In order to use these data identify the most effective siRNAs tested, it is critical adopt and develop appropriate statistical methods. To address questions in hit selection RNAi HTS, we proposed quartile-based method which robust outliers, true hits nonsymmetrical We compared with more traditional tests, mean ± k standard...
Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production the Abeta42 peptide from beta-amyloid-precursor protein (APP). Although pathogenesis more common late-onset AD (LOAD) is not understood, BACE1, protease that cleaves APP generate N terminus Abeta42, active in patients with LOAD, suggesting increased amyloid processing might also contribute sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for...
RNA interference (RNAi) high-throughput screening (HTS) has been hailed as the 2nd genomics wave following 1st of gene expression microarrays and single-nucleotide polymorphism discovery platforms.Following an RNAi HTS, authors are interested in identifying short interfering (siRNA) hits with large inhibition/activation effects.For hit selection, z-score method its variants commonly used primary HTS experiments.Recently, strictly standardized mean difference (SSMD) proposed to measure siRNA...
A macrocyclic inhibitor of beta-secretase was designed by covalently cross-linking the P1 and P3 side chains an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency physical properties when compared to initial lead structures. More importantly, these inhibitors also displayed vivo amyloid lowering dosed a murine model.