China
Africa
Explore chapters and articles related to this topic
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.
Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis
Published in Expert Review of Clinical Immunology, 2022
Since no drug has yet been approved for treating celiac disease, there is intense interest in what may constitute clinical benefit. The first two investigational drugs under development for celiac disease, larazotide and latiglutenase, both aimed to exclude bioactive gluten peptides from entering host tissues by reducing intestinal permeability or creating an additional ‘enzymic’ barrier, respectively [26,27]. Clinical development of both drugs, and others now in development, has been complicated by defining suitable trial endpoints that would eventually support marketing approval. Consequently, the companies developing larazotide and latiglutinase also produced their own separate FDA-qualified clinical outcome assessment tools for celiac disease by interviewing patients about the symptoms they recalled after gluten exposure [28].
Investigational drug therapies for coeliac disease – where to from here?
Published in Expert Opinion on Investigational Drugs, 2018
James Haridy, Diana Lewis, Evan D. Newnham
Zonulin (prehaptoglobin-2) is an epithelial tight junction protein implicated in increasing tight junction permeability. Release of zonulin in response to binding between gliadin peptides and a specific chemokine receptor (CXCR3) results in a measurable reduction in the usual intestinal barrier and allows enhanced passage of gliadin. Larazotide is a peptide derived from the zonula occludens toxin produced by the bacterium Vibrio Cholerae. This compound antagonizes the action of zonulin, and has been proposed to prevent the opening of tight junctions and related gluten-induced intestinal permeability. Larazotide is one of the few pharmaceutical treatments for CD to progress to Phase IIb studies with mixed results from three double blind, placebo-controlled trials. Initial 2-week and 6-week trials of 86 and 184 patients on a GFD displayed symptomatic improvement, however with no effect on gluten-induced intestinal permeability [43,44]. A subsequent 12-week Phase IIb trial of 342 patients met its primary end point of symptom improvement (patient reported Celiac Disease Gastrointestinal System Rating Score) compared with placebo on a modified intention to treat analysis [45]. A dose-response effect was not seen, with significant benefit encountered on the lowest of four dosages trialed. Further studies are planned to investigate this potential therapeutic benefit.
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.