|
|
Design and evaluation of potential viral methyltransferase inhibitors
Kocek, Hugo ; Nencka, Radim (advisor) ; Grantz Šašková, Klára (referee)
A global pandemic of SARS-CoV-2 confirmed the pandemic potential of the Coronaviridae family and pointed out the need for novel antiviral drugs. The SARS-CoV-2 pandemic has been tamed thanks to mRNA vaccines; however, monoclonal antibodies and small molecules such as nirmatrelvir (protease inhibitor), remdesivir (polymerase inhibitor), or molnupiravir (mutagen) are currently also available. It is worth noting that remdesivir and molnupiravir were previously investigated as antivirals against different pathogens. SARS-CoV-2 encodes 16 non-structural proteins, and two of them - methyltransferases (MTases) nsp14 and nsp16 - participate in RNA capping as the virus must mimic the host's mRNA to evade the cellular antiviral sensors (e.g., IFIT1) and replicate. These MTases are structurally very similar to those of SARS-Co-V; therefore, we might expect that inhibitors of SARS-CoV-2 MTases could be used in the future against different coronaviruses. For the reasons mentioned above, this thesis focuses on developing novel MTase inhibitors targeting SARS-CoV-2 nsp14 and nsp16. The design was based on S-adenosyl-L-homocysteine (SAH; endogenous inhibitor of MTases) and an in silico compound library was constructed with various replacements for SAH's amino acid moiety. The potential inhibitory activity was...
|
|
|
Synthesis of novel viral methyltransferase inhibitors
Kocek, Hugo ; Nencka, Radim (advisor) ; Česnek, Michal (referee)
Methyltransferases (MTases) are a class of enzymes that catalyze methylation of their substrates. These enzymes are found in all living organisms (including some viruses) as methylations are involved in numerous biological processes. Therefore, MTases are attractive targets for medicinal chemistry. Currently, only inhibitors of human MTases are used in medicine, for example, 5-azacytidine targeting DNA-MTase. However, viral MTases are potential drug targets as well. They enable viruses to escape the immune system and to use the host's translation machinery. As a consequence of the SARS-CoV-2 pandemic, coronaviral MTases became the center of attention, followed by the Mpox virus, which spread in the population in 2022. This thesis is focused on the synthesis of potential MTase inhibitors derived from adenosine-5'-carboxylic acid. The primary target is SARS-CoV-2 nsp14, however, the compound library will be used for screening against other MTases as well. Key words: methyltransferase; inhibitor; SARS-CoV-2; medicinal chemistry
|
|
|
SARS-CoV-2 methyltransferases as druggable targets
Kocek, Hugo ; Nencka, Radim (advisor) ; Bouřa, Evžen (referee)
Novel coronavirus (earlier referred to as "nCoV2019") became part of our lives in March 2020 and overnight turned everything upside-down. This virus is transmitted via respiratory droplets and causes respiratory diseases COVID-19 which can be severe and even fatal. So far, no effective treatment has been discovered and vaccination is our biggest hope thanks to its high efficacy. It is important to point out, that new mutations may possess problems and escape immunity induced by the vaccination. During the whole pandemic, many approved drugs were tested against SARS-CoV-2 (for example favipiravir, toremifene, and hydroxychloroquine) but none of those drugs showed to be effective against SARS-CoV-2 in clinical trials. The only approved antiviral drug is nucleotide analog remdesivir which showed significant efficacy against SARS-CoV-2 in clinical trials. However, timing and overall patient's health condition play a key role. Development of new antiviral drugs is necessary given the fact that this is the third time we face coronavirus with the potential to cause pandemic since the beginning of the 21st century. Therefore, it is likely that another new coronavirus will emerge. This thesis focuses on S-adenosylmethionine-dependent methyltransferases nsp14 and nsp16 from SARS-CoV-2 because they play a key...
|
guest ::
