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Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
Some progress has been made on identifying specific inhibitors against Mpro. Computer models based on X-ray crystallography showed that Mpro has three functional domains. Domains one and two contain a chymotrypsin- like domain [37], implying that the alpha-ketoamide-based protease inhibitor effective against viral 3CL-family proteases [38], may be a candidate for SARS-CoV-2 as it effectively binds to Mpro [39, 40]. Additionally, Mpro contains docking sites for HIV protease inhibitors such as lopinavir, ritonavir, and saquinavir. In fact, remdesivir, the viral RNA polymerase inhibitor can also bind to the docking site [41]. Indole-based inhibitors such as GRL-1720 are known to both interact with Mpro molecularly and to inhibit the viral infectivity of cultured cells [42]. In silico analysis identified a synthetic octopeptide AT1001 (Larazotide acetate) to interact with Mpro, which showed inhibition of this protease [43]. AT1001 is an investigational drug for ARDS [43]. Many inhibitors contain a carboxyl group, commonly seen in the design of anti-HIV proteases [44]. Recently, a GC-376 analogue was discovered with inhibitory activity against Mpro. This analogue is also active against human cathepsin L, a host protease that is important for viral entry [45]. N3, a synthetic Aza-peptide Michael acceptor inhibitor, irreversibly competes with the Mpro substrate-binding site [46]. Other candidate protease inhibitors such as ebselen, disulfiram, armofur, and PX-12 are currently being tested and have shown positive binding results with Mpro [47, 48]. Given their cost-effectiveness in production, these small molecule–based protease inhibitors may prove to be beneficial candidates in treating SARS-CoV-2 in the near future.
Colonic paracellular permeability and circulating zonulin-related proteins
Published in Scandinavian Journal of Gastroenterology, 2021
Felipe Meira de-Faria, Olga Bednarska, Magnus Ström, Johan D. Söderholm, Susanna A. Walter, Åsa V. Keita
Zonulin’s use as a potential biomarker of intestinal permeability should not be recommended due to the lack of specificity of antibodies commercially available now. Based on our data, the zonulin kit manufactured by Cusabio does not measure zonulin, as previously shown [25]. The pre-HP2 monoclonal antibody developed by Bio-Rad appears to be efficient and consistent, showing agreement with genotyping of HP genes, however, this antibody is not commercially available yet. As highlighted by others [24,25], the results of studies using the kits manufactured by Immundiagnostik and Cusabio must be viewed with caution, including our study on intestinal permeability in the elderly [34]. As aforementioned, the NH2-terminal sequence of the human zonulin published by Wang and colleagues [36] is the same sequence that was used to raise the zonulin antibody present in the Immundiagnostik kit, and to produce the peptide AT-1001 or larazotide acetate, a drug that has gone through several clinical trials already. Interestingly, a randomized study with 24 subjects has shown a very limited effect in the main endpoint results, intestinal permeability measured by lactulose‐to‐mannitol ratio [37]. In the other studies with 86 and 184 subjects, respectively [46,47], larazotide acetate failed to protect from gluten challenge-induced increased permeability.
Gut-brain communication in COVID-19: molecular mechanisms, mediators, biomarkers, and therapeutics
Published in Expert Review of Clinical Immunology, 2022
Tameena Wais, Mehde Hasan, Vikrant Rai, Devendra K. Agrawal
Zonulin increases in patients with severe infection of SARS-CoV-2 leading to increased intestinal membrane and BBB permeability. Inhibition of zonulin to prevent increased permeability is another mechanism to help prevent severe infections of SARS-CoV-2. Larazotide acetate (AT1001) is a synthetic amino acid peptide zonulin inhibitor that functions as a tight junction regulator, which is currently being clinically studied for treatment in patients with celiac disease (Figure 3c) [108]. Preventing the action of zonulin with AT1001 has been shown in many inflammatory diseases such as arthritis and Crohn’s disease to restore the impaired intestinal barrier [109,110]. Additionally, it was discovered that AT1001 also binds to the catalytic domain of the SARS-CoV-2 main protease (Mpro), which is an enzyme that is essential to viral replication [108,111]. The use of AT1001 has been clinically studied for multisystem inflammatory syndrome in children (MIS-C) that was caused by SARS-CoV-2. The children with MIS-C from SARS-CoV-2 showed high levels of zonulin leading to the increased presence of SARS-CoV-2 in the bloodstream [112]. These patients who were treated with AT1001 showed a substantial decrease in SARS-CoV-2 Spike protein antigen levels and other inflammatory markers such as IL-17, IL-2, IFN-γ, and IL-1 [112,113]. By blocking the viral replication through Mpro and preventing the action of zonulin, it leads to fewer SARS-CoV-2 particles replicating and entering the bloodstream through the intestinal barrier. Although there is an active clinical trial for AT1001 for MIS-C, more clinical studies are needed to investigate the effects of AT1001 in adults infected with COVID-19.
Duodenal inflammation: an emerging target for functional dyspepsia?
Published in Expert Opinion on Therapeutic Targets, 2020
Lucas Wauters, Grace Burns, Matthias Ceulemans, Marjorie M Walker, Tim Vanuytsel, Simon Keely, Nicholas J Talley
Besides acid and nutrient sensing in the duodenum, transmucosal passage of luminal content occurs in the proximal small intestine and is regulated by the apical junction complex consisting of tight junctions, adherens junctions, and desmosomes [98]. We have demonstrated increased duodenal mucosal permeability in FD patients using Ussing chambers (ex vivo) with a decreased expression of tight junctions (zonula occludens 1 (ZO-1) and occludin), adherens junctions (β-catenin and E-cadherin), and desmosomes (desmoglein-2), correlating with the number of mast cells and eosinophils [25]. Mucosal impedance studies (in vivo) have also shown correlations between duodenal ZO-1 and IL-1β expression with permeability [99], and IL-1β release by peripheral lymphocytes from FD patients [14] as well as human macrophages and eosinophils [100,101]. However, future studies should include protein analyses as post-translational regulation is important for both barrier- [98] and immune-related genes such as IL-1β [34]. Abnormalities of the apical junction complex have also been reported in the jejunum of diarrhea-predominant IBS patients, which were correlated with mast cell activation and clinical symptoms [102]. Expression of ZO-1 was reduced both at gene- and protein-level, with redistribution to the cytoplasm on confocal microscopy [103]. However, the cause and effect relation between immune activation and permeability is still unknown and requires interventional studies with drugs affecting the duodenal barrier function. Treatment with larazotide acetate reversed the gliadin-induced decrease in the duodenal ZO-1 expression in patients with celiac disease [104] and future trials with drugs in the novel class of tight junction regulators are awaited for FD patients. Finally, oral dietary glutamine supplements reduced symptoms and intestinal hyperpermeability, measured with the urinary lactulose–mannitol ratio in diarrhea-predominant pi-IBS patients, and therefore may have a role for alleviating symptoms in FD, although the underlying mechanisms are unclear [105].