A5022829861- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Hepatitis C virus research
- interferon and immune responses
- Click Chemistry and Applications
- HIV/AIDS Research and Interventions
- RNA and protein synthesis mechanisms
- Epigenetics and DNA Methylation
- Biochemical and Molecular Research
- Influenza Virus Research Studies
- Carbohydrate Chemistry and Synthesis
- Viral Infections and Vectors
- Histone Deacetylase Inhibitors Research
- Cancer, Lipids, and Metabolism
- Pneumocystis jirovecii pneumonia detection and treatment
- Immune Cell Function and Interaction
- COVID-19 Clinical Research Studies
- Cellular transport and secretion
- Toxoplasma gondii Research Studies
- Wnt/β-catenin signaling in development and cancer
- Chemical Synthesis and Analysis
- Virology and Viral Diseases
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Virus-based gene therapy research
Drexel University
2017-2024
Max Delbrück Center
2011-2024
Freie Universität Berlin
2015-2024
Philadelphia University
2017-2019
The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in replication (structural and regulatory). Herein, we report design synthesis three series benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications PF-74 aid discovery more potent drug-like inhibitors. Structure–activity relationship studies these compounds led identification with piperazinone...
Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors the rely on conversion acetate to acetyl-CoA enzyme synthetase 2 (ACSS2), key regulator fatty acid synthesis protein acetylation. Here, we used computational pipeline identify novel ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, excretion (ADME) property predictions. We identified...
Myxovirus resistance (Mx) GTPases are induced by interferon and inhibit multiple viruses, including influenza human immunodeficiency viruses. They have the characteristic domain architecture of dynamin-related proteins with an N-terminal GTPase (G) domain, a bundle signaling element, C-terminal stalk responsible for self-assembly effector functions. Human MxA (also called MX1) is expressed in cytoplasm partly associated membranes smooth endoplasmic reticulum. It shows protein...
Novel phenylalanine derivatives were discovered as HIV-1 capsid protein inhibitors <italic>via</italic> “click reaction”. Most of them exhibited remarkable anti-HIV-1 activity.
Orthomyxoviruses, such as influenza and thogotoviruses, are important human animal pathogens. Their segmented viral RNA genomes wrapped by nucleoproteins (NPs) into helical ribonucleoprotein complexes (RNPs). NP structures of several viruses have been reported. However, there still contradictory models how orthomyxovirus RNPs assembled. Here, we characterize the crystal structure Thogoto virus (THOV) found striking similarities to NPs, including a two-lobed domain architecture, positively...
Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of major protein homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs vitro vivo. Here, using medicinal chemistry approach, aimed improve the potency We analog, B02-isomer, which inhibits significantly higher efficiency. also show that B02-iso sensitizes triple-negative breast cancer...
Casein kinase 2 (CK2) is an evolutionarily conserved serine/threonine implicated in a wide range of cellular functions and known to be dysregulated various diseases such as cancer. Compared most other kinases, CK2 exhibits several unusual properties, including dual co-substrate specificity high degree promiscuity with hundreds substrates described date. Most paradoxical, however, its apparent constitutive activity: no definitive mode catalytic regulation has thus far been identified. Here we...
Toscana virus is an emerging bunyavirus in Mediterranean Europe where it accounts for 80% of pediatric meningitis cases during the summer. The negative-strand ribonucleic acid (RNA) genome wrapped around virally encoded nucleoprotein N to form ribonucleoprotein complex (RNP). We determined crystal structures hexameric alone (apo) and with a nonameric single-stranded RNA. RNA sequestered sequence-independent fashion deep groove inside hexamer. At junction between two adjacent copies Ns,...
Poor metabolic stability of the human immunodeficiency virus type-1 (HIV-1) capsid (CA) inhibitor PF-74 is a major concern in its development toward clinical use. To improve on stability, we employed novel multistep computationally driven workflow, which facilitated rapid design improved analogs an efficient manner. Using this designed three compounds that interact specifically with CA interprotomer pocket, inhibit HIV-1 infection, and demonstrate enantiomeric preference. Moreover, using...
HIV-1 entry inhibition remains an urgent need for AIDS drug discovery and development. We previously reported the of cyclic peptide triazoles (cPTs) that retain irreversible inactivation functions parent linear peptides (PTs) have massively increased proteolytic resistance. Here, in initial structure-activity relationship investigation, we evaluated effects variations key structural functional components cPT scaffold order to produce a platform developing next-generation cPTs. Some elements,...
Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design series of 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed residues 106-109 in HIV-1 hexamer. Compound d19 displayed excellent antiretroviral potency against and HIV-2 strains with EC
Although combination antiretroviral therapy (cART) has achieved significant success in treating HIV, the emergence of multidrug-resistant viruses and cumulative medication toxicity make it necessary to find new classes agents with novel mechanisms action. With high sequence conservation, HIV-1 capsid (CA) protein attracted attention as a prospective therapeutic target due its crucial structural regulatory functions replication cycle.Herein, authors provide cutting-edge overview current...
Optimization of compound 11L led to the identification novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 21a2 showed significant improvements, with 2.5-fold over 7.3-fold PF74 for HIV-1, approximately 40-fold The X-ray co-crystal structures confirmed multiple pocket occupation in binding site. Mechanistic studies revealed a dual-stage inhibition profile, where...
The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed series of low-molecular-weight phenylalanine derivatives. Among them, 7t exhibited remarkable antiviral activity with high selection index (EC
We report the design, synthesis, and mechanistic study of a novel series 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking structure host factors binding to CA.