Coxsackievirus and related enteroviruses are important human pathogens that cause various diseases with clinical manifestations ranging from trivial flu-like syndromes to dangerous or even fatal diseases such as myocarditis, meningitis and encephalitis. Here, we report on our continuous SAR study focused on 9-(bicyclo[2.2.1]hept-2-yl)-9H-purines as anti-enteroviral inhibitors. The purine moiety was modified at positions 2, 6 and 8. Several analogues inhibited Coxsackievirus B3 as well as other enteroviruses at low-micromolar concentrations. The 6-chloropurine derivative was confirmed as the most active compound in this series.

• MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• Cercopithecus aethiops MeSH
• Enterovirus účinky léků   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• Vero buňky MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• puriny MeSH

BACKGROUND: The longitudinal study was conducted over the initial 2 years of the COVID-19 pandemic, spanning from June 2020 to December 2022, in healthcare workers (HCWs) of the Thomayer University Hospital. A total of 3892 blood samples were collected and analyzed for total nucleocapsid (N) antibodies. The aim of the study was to evaluate the dynamics of N antibodies, their relationship to the PCR test, spike (S) antibodies, interferon-gamma, and prediction of reinfection with SARS-CoV-2. METHODS: Blood collections were performed in three rounds, along with questionnaires addressing clinical symptoms of past infection, PCR testing, and vaccination. Antibody measurements included total N antibodies (Roche Diagnostics) and postvaccination S antibodies (Euroimmun). Cellular immunity was tested by interferon-gamma release assay (Euroimmun). RESULTS: At the end of the study, 35.9% of HCWs were positive for N antibodies, and 39.5% of HCWs had either known PCR positivity or N antibodies or both. Ten percent of participants had no knowledge of a COVID-19 infection and 35% of positive individuals exhibited no symptoms. The values of positive antibodies decrease over a period of 6 months to 1 year, depending on the initial value, and their dynamics are highly variable. The study also demonstrated that the highest levels of spike antibodies and interferon-gamma occur during so-called hybrid immunity. CONCLUSION: Nucleocapsid antibodies proved valuable in monitoring SARS-CoV-2 infection dynamics, and they may detect cases of SARS-CoV-2 infection missed by PCR tests. The study identified distinct patterns in antibody dynamics and protection of hybrid immunity during reinfection.

• Klíčová slova
• COVID‐19, IGRA, SARS‐CoV‐2, hybrid immunity, nucleocapsid antibodies, serological marker, spike antibodies,
• MeSH
• biologické markery krev   MeSH
• COVID-19 * imunologie   krev   diagnóza   epidemiologie   MeSH
• dospělí MeSH
• fosfoproteiny MeSH
• glykoprotein S, koronavirus imunologie   MeSH
• interferon gama krev   MeSH
• koronavirové nukleokapsidové proteiny imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• nemocnice univerzitní MeSH
• nukleokapsida imunologie   MeSH
• protilátky virové * krev   MeSH
• SARS-CoV-2 * imunologie   MeSH
• sérologické testování na COVID-19 metody   MeSH
• zdravotnický personál * statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• fosfoproteiny MeSH
• glykoprotein S, koronavirus MeSH
• interferon gama MeSH
• koronavirové nukleokapsidové proteiny MeSH
• nucleocapsid phosphoprotein, SARS-CoV-2 MeSH Prohlížeč
• protilátky virové * MeSH

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure⁻activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host⁻target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

• Klíčová slova
• CoMSA, IVE-PLS, benzene-based carbamates, in vitro cholinesterase inhibition, molecular docking study,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• analýza hlavních komponent MeSH
• benzen chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• Electrophorus MeSH
• inhibiční koncentrace 50 MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• koně MeSH
• ligandy MeSH
• pravděpodobnost MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• benzen MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• karbamáty MeSH
• ligandy MeSH

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

• MeSH
• acetylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• katalytická doména MeSH
• lidé MeSH
• oximy chemie   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vodíková vazba MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• oximy MeSH

Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

• Klíčová slova
• Acetylcholinesterase, Nerve agents, Organophosphate, Pyridinium oximes, Reactivation, Uncharged reactivator,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• antidota chemie   farmakologie   terapeutické užití   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• lidé MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární struktura MeSH
• nervová bojová látka chemie   toxicita   MeSH
• organofosforové sloučeniny antagonisté a inhibitory   toxicita   MeSH
• otrava organofosfáty farmakoterapie   etiologie   metabolismus   MeSH
• pesticidy antagonisté a inhibitory   toxicita   MeSH
• pyridinové sloučeniny chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• reaktivátory cholinesterázy chemie   farmakologie   terapeutické užití   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• ligandy MeSH
• nervová bojová látka MeSH
• organofosforové sloučeniny MeSH
• pesticidy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH

In silico methods like molecular docking and pharmacophore modeling are established strategies in lead identification. Their successful application for finding new active molecules for a target is reported by a plethora of studies. However, once a potential lead is identified, lead optimization, with the focus on improving potency, selectivity, or pharmacokinetic parameters of a parent compound, is a much more complex task. Even though in silico molecular modeling methods could contribute a lot of time and cost-saving by rationally filtering synthetic optimization options, they are employed less widely in this stage of research. In this review, we highlight studies that have successfully used computer-aided SAR analysis in lead optimization and want to showcase sound methodology and easily accessible in silico tools for this purpose.

• Klíčová slova
• Docking, Lead optimization, Molecular modeling, Pharmacophore modeling, Structure-activity relationship,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.

• MeSH
• antimetabolity MeSH
• azosloučeniny chemická syntéza   farmakologie   MeSH
• bromodeoxyuridin MeSH
• buněčný cyklus účinky léků   MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• imunoblotting MeSH
• inhibitory enzymů chemická syntéza   farmakologie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk účinky léků   MeSH
• pyrazoly chemická syntéza   farmakologie   MeSH
• reverzní transkripce účinky léků   MeSH
• RNA biosyntéza   izolace a purifikace   MeSH
• substrátová specifita MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antimetabolity MeSH
• azosloučeniny MeSH
• bromodeoxyuridin MeSH
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy MeSH
• inhibitory enzymů MeSH
• pyrazoly MeSH
• RNA MeSH

Seroprevalence studies represent a very important tool to find out what fraction of population has already met with the new type of coronavirus (e.g. SARS-CoV-2). Without these data, it is almost impossible for the state authorities to manage the epidemic and adopt rational measures. This article brings the results of a medium-sized seroprevalence study which was carried out in the spring of 2020 in South Bohemia. In the Strakonice and Písek regions, the ELISA method was used to test the prevalence of IgA and IgG antibodies in 2011 subjects, volunteers from general public and selected professions working in areas with a higher exposure to the infection. The study showed that already in May 2020, 2.9% of inhabitants of the Strakonice region and 1.9% of inhabitants of the Písek region had antibodies against the coronavirus. These numbers imply that for each PCR positive person, there were at least fifty others who had probably already undergone the infection. The article points out three types of problems that might occur in such a study. First, the study must be planned correctly, and possible outcomes must be pre-assessed. Second, an appropriate test must be selected with known parameters. This enables us to correctly estimate the share of false positive and false negative results. Third, the data must be evaluated in a reasonable way and correct inference must be performed. We offer a set of recommendations how to manage these issues and how to solve problems that inevitably arise in such a large-scale testing.

• Klíčová slova
• COVID-19, Czech study, IgA, IgG, SARS-CoV-2, antibodies, seroprevalence,
• MeSH
• COVID-19 * diagnóza   epidemiologie   MeSH
• ELISA MeSH
• lidé MeSH
• pandemie MeSH
• SARS-CoV-2 MeSH
• séroepidemiologické studie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika * epidemiologie   MeSH

In hyperthermia, the general opinion is that pre-treatment optimization of treatment settings requires a patient-specific model. For deep pelvic hyperthermia treatment planning (HTP), tissue models comprising four tissue categories are currently discriminated. For head and neck HTP, we found that more tissues are required for increasing accuracy. In this work, we evaluated the impact of the number of segmented tissues on the predicted specific absorption rate (SAR) for the pelvic region. Highly detailed anatomical models of five healthy volunteers were selected from a virtual database. For each model, seven lists with varying levels of segmentation detail were defined and used as an input for a modeling study. SAR changes were quantified using the change in target-to-hotspot-quotient and maximum SAR relative differences, with respect to the most detailed patient model. The main finding of this study was that the inclusion of high water content tissues in the segmentation may result in a clinically relevant impact on the SAR distribution and on the predicted hyperthermia treatment quality when considering our pre-established thresholds. In general, our results underline the current clinical segmentation protocol and help to prioritize any improvements.

• Klíčová slova
• 3D patient modeling, RF hyperthermia, deep hyperthermia treatment planning, tissue delineation and segmentation,
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: Examine changes in SARS-CoV-2 seropositivity before and during the national vaccination campaign in the Czech Republic. DESIGN: Prospective national population-based cohort study. SETTING: Masaryk University, RECETOX, Brno. PARTICIPANTS: 22 130 persons provided blood samples at two time points approximately 5-7 months apart, between October 2020 and March 2021 (phase I, before vaccination), and between April and September 2021 (during vaccination campaign). OUTCOME MEASURES: Antigen-specific humoral immune response was analysed by detection of IgG antibodies against the SARS-CoV-2 spike protein by commercial chemiluminescent immunoassays. Participants completed a questionnaire that included personal information, anthropometric data, self-reported results of previous RT-PCR tests (if performed), history of symptoms compatible with COVID-19 and records of COVID-19 vaccination. Seroprevalence was compared between calendar periods, previous RT-PCR results, vaccination and other individual characteristics. RESULTS: Before vaccination (phase I), seroprevalence increased from 15% in October 2020 to 56% in March 2021. By the end of phase II, in September 2021, prevalence increased to 91%; the highest seroprevalence was seen among vaccinated persons with and without previous SARS-CoV-2 infection (99.7% and 97.2%, respectively), while the lowest seroprevalence was found among unvaccinated persons with no signs of disease (26%). Vaccination rates were lower in persons who were seropositive in phase I but increased with age and body mass index. Only 9% of unvaccinated subjects who were seropositive in phase I became seronegative by phase II. CONCLUSIONS: The rapid increase in seropositivity during the second wave of the COVID-19 epidemic (covered by phase I of this study) was followed by a similarly steep rise in seroprevalence during the national vaccination campaign, reaching seropositivity rates of over 97% among vaccinated persons.

• Klíčová slova
• COVID-19, epidemiology, public health,
• MeSH
• COVID-19 * MeSH
• kohortové studie MeSH
• lidé MeSH
• prospektivní studie MeSH
• protilátky virové MeSH
• SARS-CoV-2 * MeSH
• séroepidemiologické studie MeSH
• vakcinace MeSH
• vakcíny proti COVID-19 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• protilátky virové MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč
• vakcíny proti COVID-19 MeSH