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Recent Developments in Therapies and Strategies Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Misbah Hameed, M. Zia-Ul-Haq, Marius Moga
Ivermectin is one of the anti-anthelmintic drugs that has been used in the treatment of various infections in mammals. Ivermectin is a broad-spectrum highly lipid-soluble drug and has different effects on parasites such as nematodes, arthropods, mycobacteria, and flavivirus. A part from its good antiparasitic and antiviral activity, it can induce immunomodulatory effects in the host cells. It also inhibits the proliferation of cancer cells; it also has a role in regulating glucose and cholesterol. Ivermectin increase the influx of Cl-ions in invertebrates cell membrane by activating specific ivermectin-sensitive ion channels. The resulting hyperpolarization causes muscle paralysis of anthelmintics. It has been discovered that ivermectin inhibits the interaction between integrate molecules of human immunodeficiency virus (HIV)-1 with its nuclear transport receptor importin α/ß. Another study showed that it has the potential to hinder viral replication of some viruses, such as dengue virus, flavivirus, yellow fever virus, and influenza [67].
Order Blubervirales: Core Protein
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The most important targets of the HBc protein during HBV replication were the nuclei of infected cells, as the HBc protein shuttled between the nucleus and cytoplasm. The importin alpha and beta complexes, or importin alpha alone, were regarded therefore as potential transporters of capsids to the nuclear pores (Kann et al. 2007), where capsids interacted with nucleoporin 153 and dissociated during nuclear entry (Rabe et al. 2009; Schmitz et al. 2010).
Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
Recent investigations have identified cytosolic receptor proteins responsible for transport of NLS-containing proteins into the nucleus (Fig. 6) (127,128). These studies employing in vitro reconstitution of nuclear import showed that two cytosolic fractions were necessary and sufficient to reproduce nuclear protein import. Fraction A, associated with nuclear envelope docking activity, contains a protein heterodimer of importin-α and importin-β (128). Fraction B conferred nuclear pore translocation and has been shown to contain a GTPbinding protein called Ran/TC4, and an associated stimulatory factor called pp15. Görlich and colleagues have shown that Ran/TC4 and importin-α/β are sufficient to restore nuclear import. These cytosolic transport factors and their homologs have been the subject of extensive, ongoing investigations. Table 4 summarizes the transport factors identified to date.
Recent progress in the repurposing of drugs/molecules for the management of COVID-19
Published in Expert Review of Anti-infective Therapy, 2021
Divakar Sharma, Adinarayana Kunamneni
Ivermectin is an anti-parasitic drug (FDA-approved) that showed broad-spectrum host-centric anti-viral activity against many viruses, in-vitro [37]. It interacted with the heterodimeric importin (IMP) α/β1 and inhibited the nuclear import of key proteins host as well as viral in the coronaviruses [38,39]. An in-vitro study reported that ivermectin very efficiently cleared the SARS-CoV-2 from the infected Vero-hSLAM cells [40]. In SARS-CoV and MERS-CoV, ORF6 proteins and ORF4b proteins interacted with IMP-α respectively and access the nucleus in an NLS-dependent fashion and lead to altered mRNA splicing [41]. But ivermectin binding to IMP-α dissociated the IMP α/β1 heterodimer and block the NS5 nuclear import which further leads to normal mRNA splicing. In SARS-CoV-2 it is still unknown which ORFs protein interacted with IMP-α, various researches are ongoing in this direction. Further in-vivo research is needed to validate the in-vitro results of potential drugs against the SARS-Co-V-2. Based on these shreds of evidence ivermectin could be repurposed as a potent molecule against COVID-19.
In vivo KPT-350 treatment decreases cortical hyperexcitability following traumatic brain injury
Published in Brain Injury, 2020
David Cantu, Danielle Croker, Sharon Shacham, Sharon Tamir, Chris Dulla
Other mechanisms that can be disrupted in TBI and other neurological disorders include nuclear/cytoplasmic transport. Large macromolecules are transported into and out of the nucleus by carrier proteins called importins and exportins. The major exportin, exportin-1 (XPO1 or CRM1), carries a large number of proteins, including several related to cell injury (171819–20). XPO1 is significantly upregulated in neurons following neuronal damage in humans with severe multiple sclerosis (21) and in animal models of TBI (22) and stroke (23). Novel small molecule XPO1 inhibitors, also known as selective inhibitors of nuclear export (SINE), have recently become available and have shown promise as therapeutic targets for neurological disorders such as TBI (24) and multiple sclerosis (25).
Therapeutic options for COVID-19: a quick review
Published in Journal of Chemotherapy, 2020
Muhammad Sani Ismaila, Faruku Bande, Aminu Ishaka, Aminatu Abubakar Sani, Karla Georges
Among the literature analyzed in the present work are those focusing on the use of antiparasitic drugs like emetine and ivermectin to treat patients with COVID-19. Emetine, for example, is an isoquinoline, an alkaloid from ipecac. It has been extensively used as an antiparasitic drug reported to inhibit both ribosomal and mitochondrial protein synthesis as well as interfere with the integration and activities of DNA and RNA.80–82 Ivermectin is a broad-spectrum antiparasitic drug. The proposed anti-COVID-19 viral mechanism reported for ivermectin from the in-vitro study is by blocking importin heterodimer responsible for nuclear import. Ivermectin is originally an antiparasitic drug shown to bind with and destabilize the Impα/β1 heterodimer, thereby preventing it from binding to the viral protein and from entering the nucleus, this results in decreased inhibition of the antiviral responses, leading to more efficient antiviral response.29 In vitro experimentation in Vero/hSLAM cells infected with SARS-CoV-2 clinical isolate, Australia/VIC01/2020 (MOI = 0.1) resulted in a ∼5000-fold reduction in viral RNA at 48 h with no toxicity observed.29 But some controversy arose which made the FDA to issue a warning explaining that in vitro studies as reported in Antiviral Research (AVR) were commonly used in the early stages of drug development; thus, additional testing was needed to determine whether ivermectin might be safe or effective in preventing or treating coronavirus or COVID-19 (FDA:https://www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-ivermectin-intended-animals-treatment-covid-19-humans).