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Therapeutic Challenges in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Alaa A. A. Aljabali, Murtaza M. Tambuwala, Debmalya Barh, Kenneth Lundstrom
As proteases such as 3-chymotrypsin-like protease (3CLPro) play a role in SARS-CoV-2 replication, inhibitors such as ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin have been suggested as potential antiviral drugs for the treatment of COVID-19 patients [33]. Ivermectin, characterized for its anti-parasitic and antiviral activities, has demonstrated a 90% reduction in viral RNA levels in SARS-CoV-2 infected Vero E6 cells [34]. When subjected to clinical evaluation, ivermectin showed no superiority to placebo in non-severe COVID-19 patients in a pilot study [35]. Furthermore, a systematic review and meta-analysis of 15 clinical trials did not show reduced mortality or shortened recovery time in COVID-19 patients receiving ivermectin compared to the control group subjected to standard care [36]. The mega-analysis further revealed that the clinical trials were badly designed, biased, and provided low certainty of evidence. The papain-like protease (PLpro) is another potential target because of its involvement in viral replication [37]. Computational biology identified 147 potential SARS-CoV-2 inhibitors from the screening of FDA-approved drugs [38]. For example, the naphthalene-based PLpro inhibitor L10 inhibited coronavirus replication in Vero E6 cells [39]. The SARS-CoV-2 helicase has also been evaluated as a target for COVID-19 therapy [40]. In addition to lumacaftor, cepharatine, and bananin, flavonoid phytomedicines such as caflanone, equivir, hesperitin, quercetin, and myricetin can inhibit SARS-CoV helicase [41, 42]. The 99.8% homology between SARS-CoV and SARS-CoV-2 suggests that helicase inhibitors could be potential COVID-19 therapeutics [40].
Medicinal Plants Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Binish Khaliq, Naila Ali, Ahmed Akrem, M. Yasin Ashraf, Arif Malik, Arifa Tahir, M. Zia-Ul-Haq
COVID-19 belongs to family Coroaviridae. COVID-19 has the enveloped, positive single-stranded RNA and nucleocapsid with symmetric helical [2]. There are 20 type proteins encode in the COVID-19 virus and four major proteins, i.e., nucleocapsid, spike, envelope, and membrane protein. Instead of these main structural proteins, there are many nonstructural proteins, i.e., papain-like protease, RNA dependent RNA polymerase and coronavirus main protease [3]. In human and bat cells the angiotensin-converting enzyme-2 (ACE2) receptor is responsible to allow entry and attach with coronavirus and then replicate the virus inside the cell [4, 5]. COVID-19 virus binds to host cell through the spike protein receptor and angiotensin-converting enzyme-2 receptor of the host cell. This binding between the virus and host cell receptors triggers the changes S2 subunits at the C terminal of the spike protein. A complex between virus spike protein and ACE2 of host cell catalyzed by transmembrane serine proteases and as the result of this process the ACE2 break and viral nucleic acid enter into the host cell [6]. The viral RNA is translated into pp1a and pp1ab polyproteins after entry and uncoating. These proteins go through a proteolytic breakdown and synthesized 15 to 16 nonstructural proteins. Following the vesicle is produced by the nonstructural proteins and cellular membrane rearrangement. However, RNA nucleic acid is coded into subgenomic RNA where its synthesis of structural and other associative proteins. At last, nucleocapsids are gather in the endoplasmic reticulum and Golgi apparatus complex and after this it free through secretory pathway [7]. COVID-19 has the many genetical and clinical similarities with ß genus such as SAR coronavirus and NL63 of the coronaviruses (CoVs) [8]. For cause of disease, these viruses need their reaction with the ACE2 receptor. COVID-19 and SARS coronavirus genome has high nucleotides homology [9].
Inhibition by components of Glycyrrhiza uralensis of 3CLpro and HCoV-OC43 proliferation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Jang Hoon Kim, Yea-In Park, Mok Hur, Woo Tae Park, Youn-Ho Moon, Yun-Chan Huh, Tae IL Kim, Min Hye Kang, Jong Seong Kang, Chong Woon Cho, Junsoo Park
SARS-CoV-2, of the Coronaviridae, is a positive-sense single-stranded RNA virus with a genome of ∼30,000 nucleotides and ∼ 89.1% similarity to SARS-CoV.10 After entering the cell, the virus releases RNA, which is then translated into two polyproteins (pp1a and pp1ab).11 These have two cysteine proteases, the papain-like protease (PLpro) and the chymotrypsin-like protease (3CLpro).11 Especially, the latter is one of the most representative target enzymes for the development of SARS-CoV-2 inhibitors.12 Polyproteins are cleaved into non-structure proteins by 3CLpro, which are key factors in virus propagation.13,14 Thus, 3CLpro is a target for the development of therapeutics.15
Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed Elagawany, Ayman Abo Elmaaty, Ahmed Mostafa, Noura M. Abo Shama, Eman Y. Santali, Bahaa Elgendy, Ahmed A. Al-Karmalawy
Additionally, coronaviruses belong to RNA viruses [single-stranded positive-sense (+)] that are distinctly prevalent in wildlife and humans. Notably, coronaviruses have the most enormous known RNA genomes. Hence, the virus’s two encoded overlapping open-reading frames are translated into the two polyproteins named; pp1a and pp1ab. So, these polyproteins are processed further to give rise to four structural proteins and sixteen non-structural proteins (nsps)11. Subsequently, the virus replicase polyprotein is processed by two distinct cysteine proteases; the papain-like protease (PLpro) and the main protease (Mpro)12,13. The proteolytic refining of the sixteen nsps by PLpro and 3CLpro is crucial for virus maturation and replication, and therefore PLpro and 3CLpro emerged as key druggable targets14–18.
Delivery of MERS antigen encapsulated in α-GalCer-bearing liposomes elicits stronger antigen-specific immune responses
Published in Journal of Drug Targeting, 2022
Masood Alam Khan, Ajamaluddin Malik, Abdulmohsen M. Alruwetei, Mohammad A. Alzohairy, Bader Y. Alhatlani, Osamah Al Rugaie, Fahad A. Alhumaydhi, Arif Khan
The nanoparticle-based vaccine carriers have offered great promises in the generation of effective immune responses. Liposomes and nanoparticles have been suggested to be potent vaccine adjuvants [8]. Liposomes can deliver the encapsulated antigens to the cytoplasmic compartment of the APCs and stimulate the cell-mediated immune responses [21]. α-GalCer has been shown to activate CD4+ T cells, CD8+ T cells and NKT cells [11,22–24]. The purified MERS-CoV spike protein-bearing nanoparticles have induced the higher production of corona virus-specific antibody [25]. A MERS spike protein synthetic DNA vaccine induced the protective immunity against MERS-CoV infection in non-human primates [26]. Since papain-like protease (PLpro) is an antigen of MERS-CoV and is used by the virus to evade the innate immune response of the host [27]. Thus, it may be useful to target MERS-CoV PLpro in order to blunt the immune evasion strategy of the virus. In the present study, we prepared α-GalCer-incorporated liposomes and loaded them with MERS-CoV PLpro (α-GalCer-Lip-MERS-CoV PLpro). The immunisation with α-GalCer-Lip-MERS-CoV PLpro induced the stronger activation of antigen-specific effector and memory immune responses in mice.