RESUMO
The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors.
RESUMO
The aim of our study was to assess the performance of content-based image retrieval (CBIR) for similar chest computed tomography (CT) in obstructive lung disease. This retrospective study included patients with obstructive lung disease who underwent volumetric chest CT scans. The CBIR database included 600 chest CT scans from 541 patients. To assess the system performance, follow-up chest CT scans of 50 patients were evaluated as query cases, which showed the stability of the CT findings between baseline and follow-up chest CT, as confirmed by thoracic radiologists. The CBIR system retrieved the top five similar CT scans for each query case from the database by quantifying and comparing emphysema extent and size, airway wall thickness, and peripheral pulmonary vasculatures in descending order from the database. The rates of retrieval of the same pairs of query CT scans in the top 1-5 retrievals were assessed. Two expert chest radiologists evaluated the visual similarities between the query and retrieved CT scans using a five-point scale grading system. The rates of retrieving the same pairs of query CTs were 60.0% (30/50) and 68.0% (34/50) for top-three and top-five retrievals. Radiologists rated 64.8% (95% confidence interval 58.8-70.4) of the retrieved CT scans with a visual similarity score of four or five and at least one case scored five points in 74% (74/100) of all query cases. The proposed CBIR system for obstructive lung disease integrating quantitative CT measures demonstrated potential for retrieving chest CT scans with similar imaging phenotypes. Further refinement and validation in this field would be valuable.