Inhalable chitosan-based hydrogel as a mucosal adjuvant for hydroxychloroquine in the treatment for SARS-CoV-2 infection in a hamster model.

BACKGROUND: Effective therapy for COVID-19 remains limited. Hydroxychloroquine (HCQ) has been considered, but safety and efficacy concerns remain. Chitosan exhibits antiviral and immunomodulatory effects, yet how the combination of HCQ and chitosan performs in treating COVID-19 is unknown. METHODS: Male Syrian hamsters were inoculated intranasally with standardized stocks of the SARS-CoV-2 virus. Hamsters were allocated to saline (PBS), chitosan oligosaccharide (COS), HCQ, or COS + HCQ groups and received corresponding drugs. On days 1, 7, and 14 post-infection, two animals from each group were euthanized for sample collection. Viral loads were measured in lung homogenates. Biochemistry markers, cytokines, and immunoglobulins were analyzed from hamster sera. HCQ concentrations were compared between the blood, bronchoalveolar lavage, and lung tissues. All groups underwent histopathology exams of the lungs. Additional hamsters were treated with the same drugs to assess for toxicities to the heart and liver. RESULTS: Among all groups, viral loads in the COS + HCQ group were the lowest by day 8. The COS + HCQ group produced the highest interleukin (IL)-6 levels on day 4, and the highest IL-10, IgA and IgG levels on day 8. HCQ concentrations were higher in the COS + HCQ group's lungs than the HCQ group, despite having received half the dose of HCQ. Histopathology demonstrated earlier inflammation resolution and swifter viral clearance in the COS + HCQ group. There was no evidence of cardiac or hepatic injury in hamsters that received HCQ. CONCLUSION: In hamsters infected with the SARS-CoV-2 virus, the combination of intranasal COS and HCQ was associated with increased HCQ absorption in the lungs, more effective immune responses, without increasing the risk of hepatic or cardiac injuries.

Dynamic Changes of the Blood Chemistry in Syrian Hamsters Post-Acute COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease 2019 (COVID-19). However, the long-term health consequences of COVID-19 are not fully understood. We aimed to determine the long-term lung pathology and blood chemistry changes in Syrian hamsters infected with SARS-CoV-2. Syrian hamsters (Mesocricetus auratus) were inoculated with 105 PFU of SARS-CoV-2, and changes post-infection (pi) were observed for 20 days. On days 5 and 20 pi, the lungs were harvested and processed for pathology and viral load count. Multiple blood samples were collected every 3 to 5 days to observe dynamic changes in blood chemistry. Infected hamsters showed consistent weight loss until day 7 pi At day 5 pi, histopathology of the lungs showed moderate to severe inflammation and the virus could be detected. These results indicate that SARS-CoV-2 has an acute onset and recovery course in the hamster infection model. During the acute onset, blood triglyceride levels increased significantly at day 3 pi During the recovery course, uric acid and low-density lipoprotein levels increased significantly, but the total protein and albumin levels decreased. Together, our study suggests that SARS-CoV-2 infection in hamsters not only causes lung damage but also causes long-term changes in blood biochemistry during the recovery process. IMPORTANCE COVID-19 is now considered a multiorgan disease with a wide range of manifestations. There are increasing reports of persistent and long-term effects after acute COVID-19, but the long-term health consequences of COVID-19 are not fully understood. This study reported for the first time the use of blood samples collected continuously in a SARS-CoV-2-infected hamster model, which provides more information about the dynamic changes in blood biochemistry during the acute and recovery phases of SARS-CoV-2 infection. Our study suggests that SARS-CoV-2 infection in hamsters not only causes lung damage but also causes long-term changes in blood biochemistry during the recovery process. The study may be used by several researchers and clinicians, especially those who are studying potential treatments for patients with post-acute COVID-19 syndrome.

A siRNA targets and inhibits a broad range of SARS-CoV-2 infections including Delta variant.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on the long-term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma, and Epsilon, at picomolar ranges of IC50 in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by cotreatment in K18-hACE2-transgenic mice, accompanied by a significant prevention of virus-associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggest that C6G25S provides an alternative and effective approach to combating the COVID-19 pandemic.

Unique Sulfur-Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors.

Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.

Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants.

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.

Tone-Replacement Error Diffusion for Multitoning.

Error diffusion is an efficient halftone method for mainly being applied on printers. The promising high image quality and processing efficiency endorse it as a popular and competitive candidate in halftoning and multitoning applications. The multitoning is an extension of halftoning, adopting more than two-tone levels for the improvement of the similarity between an original image and the converted image. Yet, the banding effect, indicating the areas with discontinuous tone level, disturbs the visual perception, and thus seriously degrades image quality. To solve the banding effect, the tone-replacement strategy is proposed in this paper. As documented in the experimental results, excellent tone-similarity as that of the original image and promising reconstructed dot-distribution can be provided simultaneously. Comparing with the former banding-free methods, the apparent improvements/features suggest that the proposed method can be a very competitive candidate for multitoning applications.

Efficient halftoning based on multiple look-up tables.

Look-up table (LUT) halftoning is an efficient way to construct halftone images and approximately simulate the dot distribution of the learned halftone image set. In this paper, a general mechanism named multiple look-up table (MLUT) halftoning is proposed to generate the halftones of direct binary search (DBS), whereas the high efficient characteristic of the LUT is still preserved. In the MLUT, the standard deviation is adopted as an important feature to classify various tables. In addition, the proposed quick standard deviation evaluation is employed to yield an extremely low computational complexity in calculating the standard deviation. In the parameter optimization, the autocorrelation is adopted because it can fully characterize the periodicity of dot distribution. Experimental results demonstrate that the dot distribution generated by the proposed method approximates to that of the DBS, which enables the proposed scheme as a very competitive candidate in the copying and printing industry.