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1.
iScience ; 27(6): 110019, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38883823

RESUMO

The COVID-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting spike (S) glycoprotein-mediated viral entry is a promising strategy. To identify small molecule inhibitors that block entry downstream of receptor binding, we established a high-throughput screening (HTS) platform based on pseudoviruses. We employed a three-step process to screen nearly 200,000 small molecules. First, we identified hits that inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Counter-screening against pseudoviruses with the vesicular stomatitis virus glycoprotein (VSV-G), yielded sixty-five SARS-CoV-2 S-specific inhibitors. These were further tested against pseudoviruses bearing the MERS-CoV S glycoprotein, which uses a different receptor. Out of these, five compounds, which included the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested against pseudoviruses bearing the S glycoprotein of the Alpha, Delta, and Omicron variants as well as bona fide SARS-CoV-2. This rigorous approach revealed an unreported inhibitor and its derivative as potential broad-spectrum antivirals.

2.
EMBO Mol Med ; 16(3): 523-546, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38374466

RESUMO

Huntington's disease (HD) is an incurable inherited disorder caused by a repeated expansion of glutamines in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological symptoms. Selective downregulation of the mutant Htt gene expression is considered the most promising therapeutic approach for HD. We report the identification of small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression, and improved motor and anxiety-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier. Prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutant Htt levels by small molecules can be an effective therapeutic strategy for HD.


Assuntos
Doença de Huntington , Animais , Camundongos , Encéfalo/metabolismo , Corpo Estriado , Modelos Animais de Doenças , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Fenótipo , RNA Mensageiro/genética
3.
Commun Biol ; 4(1): 573, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990679

RESUMO

Government-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood-brain barrier (BBB). There remains an urgent need for the development of next generation OPNA therapeutics. We have developed two high-throughput screening (HTS) assays using a fluorogenic NA surrogate, O-ethyl methylphosphonyl O-4-methyl-3-cyano-coumarin (EMP-MeCyC). EMP-MeCyC detoxification and EMP-BChE reactivation screening campaigns of ~155,000 small molecules resulted in the identification of 33 nucleophile candidates, including non-quaternary oximes. Four of the oximes were reactivators of both Sarin- and VX-inhibited BChE and directly detoxified Sarin. One oxime also detoxified VX. The novel reactivators included a non-quaternary pyridine amidoxime, benzamidoxime, benzaldoxime and a piperidyl-ketoxime. The VX-inhibited BChE reactivation reaction rates by these novel molecules were similar to those observed with known bis-quaternary reactivators and faster than mono-quaternary pyridinium oximes. Notably, we discovered the first ketoxime reactivator of OP-ChEs and detoxifier of OPNAs. Preliminary toxicological studies demonstrated that the newly discovered non-quaternary oximes were relatively non-toxic in mice. The discovery of unique non-quaternary oximes opens the door to the design of novel therapeutics and decontamination agents following OPNA exposure.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/toxicidade , Oximas/farmacologia , Animais , Ativação Enzimática , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR
4.
Sci Rep ; 10(1): 20030, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208761

RESUMO

Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. However, differentiation therapy of solid tumors is a challenging issue and progress in this field is limited. We performed High Throughput Screening (HTS) using a novel dual multiplex assay to discover compounds, which induce differentiation of human colon cancer cells. Here we show that the protein arginine methyl transferase (PRMT) type 1 inhibitor, MS023, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Differentiation changes in the highly aggressive human colon cancer cell line (HT-29) were proved by proteomic and genomic approaches. Growth of HT-29 xenograft in nude mice was significantly delayed upon MS023 treatment and immunohistochemistry of tumor indicated differentiation changes. These findings may lead to development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Humanos , Camundongos , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Angew Chem Int Ed Engl ; 55(20): 6057-61, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27061357

RESUMO

The zinc-Brook rearrangement of enantiomerically enriched α-hydroxy allylsilane produces a chiral allylzinc intermediate, which reacts with retention of configuration in the presence of an electrophile. Two remarkable features of this transformation are the stereochemical outcome during the formation of the allylzinc species and the complete stereocontrol in the organized six-membered transition state, which leads to an overall and complete transfer of chirality within the reaction sequence.

6.
Org Biomol Chem ; 11(44): 7768-77, 2013 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-24121457

RESUMO

The asymmetric total synthesis of the anti-proliferative macrolide (+)-neopeltolide has been completed. The stereochemically defined trisubstituted tetrahydropyran ring was constructed via a catalytic hetero-Diels-Alder reaction creating two new chiral centers in a highly diastereoselective manner. The other key features of this synthesis included Brown's asymmetric allylation to install the requisite C-11 and C-13 stereocenters. The synthesis of the oxazole side chain consisted of a hydrozirconation of an alkynyl stannane to establish the Z stereochemistry, followed by a palladium catalyzed cross coupling to introduce the desired Z olefin in the oxazole side chain.


Assuntos
Macrolídeos/síntese química , Macrolídeos/química , Espectroscopia de Ressonância Magnética , Espectrofotometria Ultravioleta , Estereoisomerismo
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