Small Molecules Targeted to a Non-Catalytic “RVxF” Binding Site of Protein Phosphatase-1 Inhibit HIV-1

HIV-1 Tat protein recruits host cell factors including CDK9/cyclin T1 to HIV-1 TAR RNA and thereby induces HIV-1 transcription. An interaction with host Ser/Thr protein phosphatase-1 (PP1) is critical for this function of Tat. PP1 binds to a Tat sequence, Q35VCF38, which resembles the PP1-binding “RVxF” motif present on PP1-binding regulatory subunits. We showed that expression of PP1 binding peptide, a central domain of Nuclear Inhibitor of PP1, disrupted the interaction of HIV-1 Tat with PP1 and inhibited HIV-1 transcription and replication. Here, we report small molecule compounds that target the “RVxF”-binding cavity of PP1 to disrupt the interaction of PP1 with Tat and inhibit HIV-1 replication. Using the crystal structure of PP1, we virtually screened 300,000 compounds and identified 262 small molecules that were predicted to bind the “RVxF”-accommodating cavity of PP1. These compounds were then assayed for inhibition of HIV-1 transcription in CEM T cells. One of the compounds, 1H4, inhibited HIV-1 transcription and replication at non-cytotoxic concentrations. 1H4 prevented PP1-mediated dephosphorylation of a substrate peptide containing an RVxF sequence in vitro. 1H4 also disrupted the association of PP1 with Tat in cultured cells without having an effect on the interaction of PP1 with the cellular regulators, NIPP1 and PNUTS, or on the cellular proteome. Finally, 1H4 prevented the translocation of PP1 to the nucleus. Taken together, our study shows that HIV- inhibition can be achieved through using small molecules to target a non-catalytic site of PP1. This proof-of-principle study can serve as a starting point for the development of novel antiviral drugs that target the interface of HIV-1 viral proteins with their host partners

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

It has now been demonstrated that the μ, δ(1), δ(2), and κ(1) opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusion‐induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia‐induced arrhythmias

Novel Echocardiographic Biomarkers in the Management of Atrial Fibrillation

Purpose of Review: Atrial fibrillation (AF) is the most common arrhythmia in adults. The number of patients with AF is anticipated to increase annually, mainly due to the aging population alongside improved arrhythmia detection. AF is associated with a significantly elevated risk of hospitalization, stroke, thromboembolism, heart failure, and all-cause mortality. Echocardiography is one of the key components of routine assessment and management of AF. Therefore, the aim of this review is to briefly summarize current knowledge on “novel” echocardiographic parameters that may be of value in the management of AF patients. Recent Findings: Novel echocardiographic biomarkers and their clinical application related to the management of AF have been taken into consideration. Both standard parameters such as atrial size and volume but also novels like atrial strain and tissue Doppler techniques have been analyzed. Summary: A number of novel echocardiographic parameters have been proven to enable early detection of left atrial dysfunction along with increased diagnosis accuracy. This concerns particularly experienced echocardiographers. Hence, these techniques might improve the prediction of stroke and thromboembolic events among AF patients and need to be further developed and disseminated. Nonetheless, even the standard imaging parameters could be of significant value and should not be discontinued in everyday clinical practice. © 2019, The Author(s)

Effective post-acceleration of ion bunches in foils irradiated by ultra-intense laser pulses

Two-step laser acceleration of protons with two foils and two laser pulses is modelled and optimized. It is shown that a nearly mono-energetic distribution of proton bunches can be realized by a suitable parameter choice. Two-step acceleration schemes make it possible to obtain both higher efficiency and energy as compared to the acceleration with only one laser pulse of an energy equal to the sum of the energy of the two pulses. With the aid of our analytical model, the optimal distance between the two targets, the delay between the two laser pulses, and the parameters of the laser pulses are determined. Estimates and results of the modelling are proven with 2D PIC simulations of the acceleration of proton bunches moving through the second target.1111sciescopu