A5023220693- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Biochemical and Molecular Research
- Endoplasmic Reticulum Stress and Disease
- Click Chemistry and Applications
- Autophagy in Disease and Therapy
- HIV/AIDS Research and Interventions
- Cancer, Hypoxia, and Metabolism
- Cytokine Signaling Pathways and Interactions
- Pneumocystis jirovecii pneumonia detection and treatment
- Carbohydrate Chemistry and Synthesis
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- Glycosylation and Glycoproteins Research
- Glutathione Transferases and Polymorphisms
- Mitochondrial Function and Pathology
- Chemokine receptors and signaling
- RNA modifications and cancer
- ATP Synthase and ATPases Research
- Quinazolinone synthesis and applications
- Cancer Treatment and Pharmacology
- HER2/EGFR in Cancer Research
- Transgenic Plants and Applications
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
University of Michigan
2016-2025
Cairo University
2024
U-M Rogel Cancer Center
2018-2020
University of Southern California
2007-2019
Michigan Center for Translational Pathology
2015-2019
Michigan Medicine
2018
Chulalongkorn University
2018
Ann Arbor Center for Independent Living
2018
Institute of Medicinal Plant Development
2012-2016
LAC+USC Medical Center
2013
Integrins are heterodimeric, transmembrane receptors that function as mechanosensors, adhesion molecules and signal transduction platforms in a multitude of biological processes. As such, integrins central to the etiology pathology many disease states. Therefore, pharmacological inhibition is great interest for treatment prevention disease. In last two decades several integrin-targeted drugs have made their way into clinical use, others trials still more showing promise they advance through...
The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 suppressor pathway promoting cell survival. Targeting has emerged as validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking N-terminal fragment have been shown be potent Hdm2/HdmX antagonists. potential use these peptides, however, limited their poor stability bioavailability. Here, we report engineering cyclotide MCoTI-I efficiently...
Protein disulfide isomerase (PDI), an endoplasmic reticulum chaperone protein, catalyzes bond breakage, formation, and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, there a need for potent, selective, safe small-molecule inhibitors PDI. Here, we report class propynoic acid carbamoyl methyl amides (PACMAs) that are active against panel human cell lines. Using fluorescent derivatives, 2D gel electrophoresis, MS, established PACMA 31, one the most...
The structures of a large number HIV-1 integrase inhibitors have in common two aryl units separated by central linker. Frequently at least one these moieties must contain 1,2-dihydroxy substituents order to exhibit high inhibitory potency. ability o-dihydroxy-containing species undergo situ oxidation reactive quinones presents potential limitation the utility such compounds. recent report tetrameric 4-hydroxycoumarin-derived inhibitor 5 provided lead example an which does not catechol...
Chromatin condensation and nuclear envelope breakdown are characteristic features of apoptotic cell death, but the mechanisms underlying these phenomena have not been identified. Solubilization lamin is responsible for both events in mitosis. In this work, we report that glucocorticoids stimulate rapid degradation B1 occurs before oligonucleosomal DNA fragmentation thymocytes. Protease inhibitors Ca2+ buffering agent BAPTA-AM block fragmentation, indicating processes regulated by similar or...
We have previously reported the inhibitory activity of curcumin against human immunodeficiency virus type one (HIV-1) integrase. In present study, we synthesized and tested analogs to explore structure-activity relationships mechanism action this family compounds in more detail. found that two analogs, dicaffeoylmethane (6) rosmarinic acid (9), inhibited both activities integrase with IC50 values below 10 microM. demonstrated lysine 136 may play a role viral DNA binding. equivalent potencies...
Seventeen lichen acids comprising despides, depsidones, and their synthetic derivatives have been examined for inhibitory activity against HIV-1 integrase, two pharmacophores associated with inhibition of this enzyme identified. A search the NCI 3D database approximately 200,000 structures yielded some 800 compounds which contain one or other pharmacophore. Forty-two these were assayed integrase inhibition, these, 27 had IC50 values less than 100 microM; 15 below 50 microM. Several also...
Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to DNA adducts are sensitive alkylating agents. Importantly, cancer cells higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards cell mitochondria based on Δψmt could overcome those limitations. Herein, we describe the design, synthesis, evaluation of Mito-Chlor,...
Herein, we report for the first time design and synthesis of a novel cyclotide able to efficiently inhibit HIV-1 viral replication by selectively targeting cytokine receptor CXCR4. This was accomplished grafting series topologically modified CVX15 based peptides onto loop 6 MCoTI-I. The most active compound produced in this study potent CXCR4 antagonist (EC50 ≈ 20 nM) an efficient cell-entry blocker 2 nM). also showed high stability human serum, thereby providing promising lead type...
Abstract GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis folding, which results in significant on the ER. To respond to ER maintain cellular homeostasis, activate unfolded response (UPR) that promotes either survival or apoptotic death. utilize UPR promote growth. In this study, we describe discovery series novel hydroxyquinoline inhibitors. A...
Abstract Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides viable approach inducing anti-tumor response, it remains unknown how effectively trigger ICD addressing immunosuppressive TAMCs. Here, we show that SC144, gp130 inhibitor blocks the IL-6/gp130/STAT3 pathway, induces of tumor and polarizes...
The 4-aryl-2-hydroxy-4-oxo-2-butenoic acids and their isosteric tetrazoles are among an emerging class of aryl beta-diketo (ADK)-based agents which exhibit potent inhibition HIV-1 integrase (IN)-catalyzed strand transfer (ST) processes, while having much reduced potencies against 3'-processing (3'-P) reactions. In the current study, L-708,906 (10e) 5CITEP (13b), two examples ADK inhibitors that have been reported by Merck Shionogi pharmaceutical companies, served as model leads. Structural...
Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme an important target for the development therapeutics against HIV infection. In fact, S-1360, first clinically used IN inhibitor containing triazole ring bioisostere carboxylic acid moiety belongs to class compounds. To understand divalent metal-chelating inhibition (J. Med. Chem. 2002, 45, 5661−5670), we designed and synthesized series novel dimeric diketo-containing...
Starting from a known inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN); caffeic acid phenethyl ester (CAPE), putative three-point pharmacophore for binding inhibitors to IN was derived. This used search the National Cancer Institute three-dimensional (3D) structural database. Out open, nonproprietary part this database, comprising approximately 200000 compounds, 267 structures were found match in at least one conformation, and 60 those tested an vitro assay against...
The human immunodeficiency virus type one integrase (HIV-1 integrase) is required for integration of a double-stranded DNA copy the viral RNA genome into host chromosome and HIV replication. We have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE), tyrphostins, curcumin confer inhibitory activity against HIV-1 integrase. investigated actions several recently described protease inhibitors, possessing novel structural features, on...
The present study was undertaken to examine structural features of L-chicoric acid (3) which are important for potency against purified HIV-1 integrase and reported cytoprotective effects in cell-based systems. Through a progressive series analogues, it shown that enantiomeric D-chicoric (4) retains inhibitory equal its L-counterpart further removal either one or both carboxylic functionalities results essentially no loss potency. Additionally, while two caffeoyl moieties required,...