Structure Characterization of Zinc Finger Motif 1 and 2 of GLI1 DNA Binding Region.

As a transcription factor, GLI1 plays an important role in cell cycle regulation, DNA replication, and DNA damage responses. The aberrant activation of GLI1 has been associated with cancers such as glioma, osteosarcoma, and rhabdomyosarcoma. The binding of GLI1 to a specific DNA sequence was achieved by five tandem zinc finger motifs (Zif motifs) on the N-terminal part of the molecule.

4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses.

2-(Methylthio)--(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC = 0.6 μM; EC = 0.93 μM and viral titer reduction (VTR) of 6.

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The disruption of dopamine neurotransmission by the HIV-1 Transactivator of transcription (Tat) during HIV-1 infection has been linked to the development of neurocognitive disorders, even under combined antiretroviral therapy (cART) treatment. We have demonstrated that SRI-32742, a novel allosteric modulator of dopamine (DA) transporter (DAT), attenuates cocaine- and Tat-binding to DAT, alleviates Tat-induced cognitive deficits and potentiation of cocaine reward in inducible Tat transgenic mice. The current study determined the pharmacological profile of SRI-32743 and its optimized second-generation analogs and their effects as allosteric modulators.

Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter.

Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments.

Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-β toxicity and network hyperexcitability.

Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-β-induced dysfunction in preclinical models of AD and also prevents amyloid-β-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD.