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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
Coronavirus enters human cells by binding its viral spike protein to the membrane-bound form of the monocarboxypeptidase angiotensin-converting enzyme 2 (ACE2). ACE2 is important in regulating the renin-angiotensin-aldosterone system (RAAS), as it metabolizes angiotensin II to produce angiotensin-(1–7). Animal studies have shown that angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) can control ACE2 expression, thus can increase the availability of target molecules for COVID-19 virus [53].
Risk factors – Treatable traits
Published in Vibeke Backer, Peter G. Gibson, Ian D. Pavord, The Asthmas, 2023
Vibeke Backer, Peter G. Gibson, Ian D. Pavord
Respiratory infection triggers a host immune response. Respiratory viral infections target the airway epithelium and enter via shared host-viral entry receptors. For example, the SARS-CoV-2 uses the host ACE2 receptor for viral entry. The host response involves activating an innate immune response involving inflammasome activation that leads to production of cytokines such as IL-1beta and IL-6, which cause acute inflammation and neutrophil recruitment. In addition, there is a host interferon response which controls viral replication and aids resolution of the infection. People with poorly controlled asthma may have a relatively deficient interferon response which allows for increased viral penetration and infection in the bronchi and an enhanced inflammatory neutrophilic response. These features contribute to the exaggerated, and at times fatal, asthmatic response that occurs with respiratory viral infections in people with asthma.
Biology of Coronaviruses and Predicted Origin of SARS-CoV-2
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Giorgio Palù, Alberto Reale, Nicolas G. Bazan, Pritam Kumar Panda, Vladimir N. Uversky, Murat Seyran, Alaa A. A. Aljabali, Samendra P. Sherchan, Gajendra Kumar Azad, Wagner Baetas-da-Cruz, Parise Adadi, Murtaza M. Tambuwala, Bruce D. Uhal, Kazuo Takayama, Ángel Serrano-Aroca, Tarek Mohamed Abd El-Aziz, Adam M. Brufsky, Kenneth Lundstrom
The structure of SARS-CoV-2 particles has been determined by cryo-electron tomography and microscopy, which identified approximately 125 nm spherical particles with prominent club-shaped spike proteins [34]. The helically symmetrical N protein enwraps the RNA genome, the triple-spanning membrane M protein binds to the N protein, while the small E protein, with a postulated transmembrane structure and ion channel activity, is associated with the assembly and release of viral particles. Furthermore, the E protein has been identified as an essential virulence factor in other CoVs, including SARS-CoV [35]. Specifically, the PDZ-binding motif (PBM) of the E protein, a domain involved in protein–protein interaction, plays a role in pathogenicity [36]. In the human OC43 coronavirus, this protein has also been linked to neurovirulence [37]. The S protein mediates the attachment to the host cell angiotensin-converting enzyme 2 (ACE2) receptor. In the case of SARS-CoV-2, a host cell furin-like protease cleaves the S protein into S1 and S2 polypeptides. There is evidence that both ACE2 as well as transmembrane protease serine 2 (TMPRSS2) may be segregated in membrane microdomains and the SARS-CoV-2 entry might be facilitated by tetraspanins, transmembrane proteins clustered in membrane microdomains [38]. These microdomains are not lipid rafts as they lack glycosyl-phosphatidylinositol (GPI)-linked proteins, caveolin and Src-kinases [39].
Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2
Published in mAbs, 2023
Meghan M. Verstraete, Florian Heinkel, Janessa Li, Siran Cao, Anh Tran, Elizabeth C. Halverson, Robert Gene, Elizabeth Stangle, Begonia Silva-Moreno, Sifa Arrafi, Jegarubee Bavananthasivam, Madeline Fung, Mariam Eji-Lasisi, Stephanie Masterman, Steve Xanthoudakis, Surjit Dixit, John Babcook, Brandon Clavette, Mark Fogg, Eric Escobar-Cabrera
The concept of using ACE2 as a therapeutic was first propelled by Apeiron Biologics which developed recombinant ACE2, APN01 (GSK2586881), in response to the SARS outbreak in 2003.48 Application of recombinant ACE2 (APN01) for treatment of SARS-CoV-2 has since been revisited by the company. Recombinant ACE2 theoretically has two mechanisms of action, one to serve as a decoy receptor for viral spike protein49 and second to attenuate pathology from SARS-CoV-2-induced hyperactivated renin-angiotensin system (RAS) through function of ACE2 catalytic activity.50 ACE2 is a negative regulator of RAS, and through catalytic cleavage of angiotensin I and II to angiotensin-(1–7) has vasodilatory, antiproliferative, antiangiogenic, and anti-inflammatory properties.51,52 The COVID-19 Phase 2 clinical trial (NCT04335136) demonstrated that treatment with APN01 was safe and that patients showed improvement on several clinical parameters, but it failed to meet clinical endpoints.49,53 We speculate that this could have at least in part been due to the relatively low affinity of monomeric ACE2 for spike protein (15–44 nM)35,40,41 and the intravenous (IV) route for administration used in the trial.
The benefits of Vitamin D in the COVID-19 pandemic: biochemical and immunological mechanisms
Published in Archives of Physiology and Biochemistry, 2023
Hadis Musavi, Omid Abazari, Zeinab Barartabar, Fatemeh Kalaki-Jouybari, Mohsen Hemmati-Dinarvand, Parisa Esmaeili, Soleiman Mahjoub
New hypotheses have emerged in treating patients with COVID-19, which has led to various studies and theories about inhibiting RAS and angiotensin receptors in these patients (Wu and Mcgoogan 2020). Patients with diabetes, hypertension, proteinuria, chronic kidney disease, cerebrovascular disease, and coronary heart abnormalities are usually treated with RAS blockers, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) (Fang et al. 2020). Recent trials have proved that ACE inhibitors and ARBs alter the expression of ACE2 and its effect on the heart and kidneys (Ferrario et al. 2005, Soler et al. 2009, Wang et al. 2016). Studies have verified that SARS-COV-2 infection downregulates the ACE2 and leads to increased toxicity of Ang II accumulation resulting in acute respiratory syndrome and myocarditis (Hanff et al. 2020, Sun et al. 2020). In patients with COVID-19, an increase and accumulation of Ang II develop inflammatory cytokines and cause severe damage. Recent experiments show that ACEI/ARB remedy reduces inflammatory cytokines and reduces the risk of pneumonia and heart disease in patients. Therefore, the ACEI/ARB prescription may be efficacious in COVID-19 patients (Hsu et al. 2020).
Association between hypertension and prognosis of patients with COVID-19: A systematic review and meta-analysis
Published in Clinical and Experimental Hypertension, 2022
Zhe Qian, Zhuohong Li, Jie Peng, Qiqing Gao, Shaohang Cai, Xuwen Xu
The relationship between SARS-COV-2 and hypertension is not yet clear. It has been established that SARS-CoV-2 invaded human cells through angiotensin-converting enzyme 2 (ACE2), a membrane-bound aminopeptidase on lung alveolar epithelial cells. Interestingly, ACE2 plays a vital role in the cardiovascular and immune systems and is always associated with hypertension. A recent study (24) concluded that ACE2 expression was increased in the lungs of COVID-19 patients with comorbidities (such as hypertension, diabetes, and chronic obstructive lung disease) and was associated with severe conditions. The study claimed that the increased ACE2 expressions in lungs, which facilitated the entry of SARS-CoV-2 into lung cells during infection, was associated with a higher risk of progression into severe COVID-19. Another study (25) suggested that COVID-19 patients with hypertension were related to delayed viral clearance and aggravated airway inflammation and might benefit from angiotensin-converting-enzyme inhibitors (ACEIs) treatments. However, other studies reported that ACEIs or angiotensin II receptor blockers (ARBs) treatments would not change the incidence of COVID-19 among hypertensive patients compared to other anti-hypertension drugs use (26,27). What is more, in another published meta-analysis (28), it was demonstrated that ACEIs or ARBs treatments had potential protective effects in COVID-19 prognosis. Therefore, the molecular relationship between SARS-COV-2 and hypertension warrants further exploration.