The rampageous transmission of SARS-CoV-2 has been devastatingly impacting human life and public health since late 2019. The waves of pandemic events caused by distinct coronaviruses at present and over the past decades have prompted the need to develop broad-spectrum antiviral drugs against them. In this study, our Pentarlandir ultrapure and potent tannic acids (UPPTA) showed activities against two coronaviral strains, SARS-CoV-2 and HCoV-OC43, the earliest-known coronaviruses. The mode of inhibition of Pentarlandir UPPTA is likely to act on 3-chymotrypsin-like protease (3CLpro) to prevent viral replication, as supported by results of biochemical analysis, a 3CLpro assay, and a “gain-of-function” 3CLpro overexpressed cell-based method. Even in the 3CLpro overexpressed environment, Pentarlandir UPPTA remained its antiviral characteristic. Utilizing cell-based virucidal and cytotoxicity assays, the 50% effective concentrations (EC 50 ) and 50% cytotoxicity concentration (CC 50 ) of Pentarlandir UPPTA were determined to be ∼0.5 and 52.5 μM against SARS-CoV-2, while they were 1.3 and 205.9 μM against HCoV-OC43, respectively. In the pharmacokinetic studies, Pentarlandir UPPTA was distributable at a high level to the lung tissue with no accumulation in the body, although the distribution was affected by the food effect. With further investigation in toxicology, Pentarlandir UPPTA demonstrated an overall safe toxicology profile. Taking these findings together, Pentarlandir UPPTA is considered to be a safe and efficacious pancoronal antiviral drug candidate that has been advanced to clinical development.

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Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease affecting many cellular pathways, including protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation. Currently, no effective treatment for AD exists. Objective: We aim to determine the effect of lithium benzoate (LiBen) in protecting neurons from amyloid-β (Aβ) or other neurotoxin insults. Methods: Primary rat cortical neurons were co-treated with neurotoxins and LiBen were used to examine its effect in cell viability, reactive oxygen species (ROS) clearance, and mitochondria functions by MTT, CellRox fluorescence staining, and seahorse assay. Then, Barnes maze and prepulse inhibition test were performed in APP/PS1 mice that received chronic LiBen treatment to assess its effect on cognitive protection. Oral bioavailability of LiBen was also assessed by pharmacokinetic study in rat plasma. Results: In this study, we discovered that LiBen can attenuate cellular ROS level, improve mitochondrial function, increase cell viability against multiple different insults of mitochondrial dysfunction, Aβ accumulation, and neuroinflammation, and promote neurogenesis. We demonstrated that LiBen has advantages over lithium or sodium benzoate alone as LiBen displays superior neuroprotective efficacy and oral bioavailability than the other two agents when being applied either alone or in combination. Furthermore, chronic administration of LiBen showed protection for cognition as well as spatial memory and reduced the senile plaque deposition in brains of AD animal models. Conclusion: LiBen stands as a promising therapeutic agent for delaying the progression of and improving cognition in AD.

C 6 H 14Cl 4 N 2 Zn, monoclinic, P 121 / c 1(no. 14), a =9.5046(3) Å, b =6.7260(1) Å, c =18.2493(4) Å, Source of materialThe title compound wass ynthesized by heating the mixture of DABCO,ZnCl 2 ,hydrochloric acid in amolarratio of 1:1:2. The solution of the compound in water wasconcentrated gradually at room temperature to afford colorless blocks. Experimental detailsThe Hatoms attaching the Natoms were located from the Fourier difference map, and refined freely. All other Hatoms were positioned geometrically and refined using ariding model with isotropic displacement parameters equalt o1 .2U eq of their parent atoms. The C-Hdistances were fixed at0.99 Åfor methylene groups. Discussion

Purpose: Malignant melanoma is a common malignant tumor in dog. It is a fatal disease with local invasiveness and frequently metastatic propensity and the poor response has been observed. The aim of this study was to establish the drug-screening platform and used that platform to evaluate small molecular inhibitor, Dasatinib, for therapy of canine melanoma. Experimental Design: Various phenotypes of eight canine melanoma cell lines, CM01, M1, M3, M4, M5, Pu, C1 and KMeC, were examined in this study. Mutation analysis of kit, Nras and Braf was done by PCR/DNA sequencing. Expression of S100, KIT and KIT downstream signaling cascades NRAS, phospho-ERK and phospho-AKT were evaluated by immunocytochemistry. KMeC, M5 and CM01 cell lines were selected for further evaluation of Dasatinib. Proliferation assay and wound healing assay were performed to assess cell viability and motility in the presence of dasatinib. Cell cycle analysis and Annexin V apoptosis assay were also applied to realize the mechanism of cell death caused by Dasatinib. Results: Expressions of S100 and KIT were observed in all of the cell lines. NRAS and activated ERK were identified in several cell lines with different expression levels. However, no activated AKT was identified in any cell lines. kit T1736C mutation causing KIT L579P change was detected in M3, KMeC and C1 cells, while Nras C181A mutation causing NRAS Q61K change was found in M5 cell. ERK activity in KMeC (KIT L579P), M5 (NRAS Q61K) and CM01 (KIT & NRAS wild type) cells was down-regulated when Dasatinib was administered. Dasatinib reduced cell viability with the IC50 values of 0.64 μM in KMeC, 0.24 μM in M5 and 0.37 μM in CM01 cells. In wound healing assay, Dasatinib inhibited cell motility in all of the three cell lines. Cell cycle analysis and Annexin V apoptosis assay revealed that the treatment of Dasatinib causes a G1 cell cycle arrest and induction of apoptosis. The analysis of Dasatinib caused signaling change in canine melanoma cell is ongoing. Conclusions: Various phenotypes of eight canine melanoma cell lines were identified in DNA and protein levels. The NRAS Q61K mutation was first found in canine melanoma. The results showed that KIT L579P mutant type, NRAS Q61K mutant type and wild type canine melanoma cells are sensitive to the treatment of Dasatinib. It caused the reduction of cell viability, and inhibition of motility, moreover, the promotion of G1 cell cycle arrest and cell apoptosis. Dasatinib may potentially be selected as a candidate for therapy of canine melanoma. Citation Format: Lu-Ping Lu, Chen-Si Lin, Albert Taiching Liao. The effects of dasatinib in KIT L579P and NRAS Q61K mutant canine melanoma cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B36.