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Computational Biology and Bioinformatics in Anti-SARS-CoV-2 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Cathepsin L, which is involved in SARS-CoV-2 endocytosis entry [112], serves as one more potential therapeutic option for COVID-19 [113]. The main entry pathway for SARS-CoVs is receptor-mediated endocytosis, in which adaptor-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK) play key roles in receptor-mediated endocytosis and clathrin-mediated trafficking, respectively. Since AAK1 and GAK regulate intracellular viral trafficking during entry, assembly, and release of RNA viruses, inhibition of their activity represents a promising therapy for COVID-19 [87]. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) synthesized in late endosomes by the phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates the dynamic process of endosome maturation [114, 115]. Therefore, inhibition of PIKfyve represents a useful strategy to modulate infection by SARS-CoV-2 and viruses that enter through endocytosis [116].
A patent review of adaptor associated kinase 1 (AAK1) inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Belén Martinez-Gualda, Dominique Schols, Steven De Jonghe
The design and synthesis of highly selective kinase inhibitors has been a challenging endeavor, since the ATP binding site is highly conserved across the kinome. A few of the patented AAK1 inhibitors have been profiled more extensively and shown to be selective when tested against a broad panel of various targets (including enzymes and receptors). However, all published AAK1 inhibitors are also equally active as BIKE inhibitors, which is not surprising given the high structural similarity of both ATP binding sites. Moreover, several published AAK1 inhibitors display also potent GAK inhibition. This inhibition of other biologically relevant kinases might be suggestive for a problematic side-effect profile. It can also be a reason that only few companies initiated AAK1 drug discovery programs. Based on the current chemotypes, it will be difficult to achieve AAK1 selectivity, especially since the known AAK1 inhibitors are type I kinase inhibitors. Future research might therefore focus on alternative modes of AAK1 inhibition, by the synthesis and design of type II, III or IV AAK1 inhibitors. On the other hand, because of the redundancy in biological functions of different members of the NAK family, the availability of pan-NAK inhibitors might be beneficial.
Unraveling the role of oxidative stress and lipid status parameters in the onset of preeclampsia
Published in Hypertension in Pregnancy, 2021
Petar Cabunac, Nataša Karadžov Orlić, Daniela Ardalić, Gorica Banjac, Jasmina Ivanišević, Jelena Janać, Jelena Vekić, Aleksandra Zeljković, Marija Mihajlović, Nina Rajović, Nataša Milić, Željko Miković
The study was conducted as a prospective cohort study from January 2016 to August 2018 at the Department of High-Risk Pregnancies, Gynecology and Obstetrics Clinic “Narodni Front”, Belgrade, Serbia. The study was approved by the Ethics Committee of GAK “Narodni Front” (24/55-5). All women were informed about the study goals and provided signed informed consent to participate.