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Airway Epithelial and Early Innate Immune Responses toVirus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Alan Chen-Yu Hsu, Su-Ling Loo, Faezeh Fathi Aghdam, Kristy Parsons, Philip M. Hansbro, Peter A. B. Wark
Influenza viruses have also developed mechanisms to inhibit host innate antiviral responses, which promote productive infection. The influenza genome encodes a protein called nonstructural (NS) 1 that inhibits RIG-I-induced activation of IRF3, thereby suppressing type I and III IFN responses.94 NS1 also binds to cellular antiviral ISGs such as PKR to prevent viral RNA degradation and apoptosis.95–99 As numerous strains of influenza viruses occur, their host’s antiviral inhibitory ability also varies. Seasonal human influenza H3N2 has been shown to carry a potent NS1 protein that more effectively inhibits antiviral responses and leads to a more productive viral replication compared to that of low pathogenic avian influenza.100 In contrast, the NS1 protein of the highly pathogenic avian H5N1 is able to completely suppress antiviral responses in BECs and DCs.101–106 In addition to the suppression of antiviral responses, the NS1 protein also reduces host protein synthesis by binding to cleavage and polyadenylation specificity factor subunit 30 (CPSF30) and poly A binding protein (PAB) II, thereby controlling the host machinery for viral replication and infection.
Chemical Hybridization Approaches Applied to Natural and Synthetic Compounds for the Discovery of Drugs Active Against Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Elena Petricci, Paolo Governa, Fabrizio Manetti
In another study, experimental evidence showing both benzoxaborole and chalcone derivatives as antitrypanosomal agents prompted the researchers to design, synthesize, and test toward bloodstream form of T. brucei many hybrid derivatives that contained the two moieties (Figure 11) (Qiao et al. 2012). The most simple (unsubstituted) benzoxaborole-chalcone derivative showed an IC50 = 89 ng/mL (that represented the ability to inhibit growth of the T. brucei 427 strain), and a selectivity index higher than 100 in mouse lung fibroblasts L929. Insertion of small substituents at the para position of the pendant phenyl ring resulted in improved activity in many cases. As examples, a Me, Et, OMe, SMe, Cl, and OH groups gave activity in the range between 43 and 71 ng/mL, with a primary amino group as in 46 being the most profitable substituent (24 ng/mL). Changing the substitution pattern at the phenyl ring yielded many compounds with IC50 values lower than 60 ng/mL. A methoxy group in position 3 as in 47 was the best substituent (22 ng/mL with a selectivity index higher than 450). Fortunately, the obvious combination of the p-NH2 with the m-OMe groups as in 48 led to a further improvement of activity (10 ng/mL), even if a higher cytotoxicity (1450 ng/mL) consequently resulted in a decrease of the selectivity index (145). Further attempts to modify the scaffold of the benzoxaborole-chalcone core (such as the reduction of the carbonyl group to an alcohol side chain, or replacement of the heterocyclic moiety with a phenyl ring) were unfruitful and yielded compounds with low or very low activity. A selection of 12 compounds active in in vitro assays was administered (50 mg/kg, twice a day, intraperitoneally) to female BALB/c mice infected with 600 T. brucei parasites. In agreement with in vitro results, 47 and 48 allowed eradication of parasites 30 days after infection and led to 100% survival. Although impressive in vitro and in vivo results were reached by these two compounds, their mechanism of action and cellular target were not further investigated. Very recently, benzoxaborole derivatives bearing simple substituent (such as a F in position 5) (Manhas et al. 2018), a substituted benzamide side chain or more complex appendages at position 6 (Wall et al. 2018) showed antiparasitic activity by targeting L. donovani leucyl-tRNA synthetase, or the T. brucei cleavage and polyadenylation specificity factor 3, respectively, laying the foundations for the discovery of molecular targets of these useful compounds. Benzoxaborole-chalcone hybrids as antitrypanosomal agents.
Treatment of cryptosporidiosis: nitazoxanide yes, but we can do better
Published in Expert Review of Anti-infective Therapy, 2023
Maria A. Caravedo, A. Clinton White
Other groups have identified parasite molecules as targets for chemotherapy and developed specific inhibitors. Screening compounds that inhibit cleavage and polyadenylation specificity factor 3 identified several oxaborole compounds that are now in preclinical development [60] The parasite calcium-dependent protein kinase 1 is an attractive target for drug development. A range of active inhibitors were identified that were effective in vitro and in animal models. However, unanticipated toxicities have precluded these compounds from advancing into clinical trials [48,61] Other parasite molecules including inosine monophosphate dehydrogenase, thymidylate-synthetase dihydrofolate reductase, tRNA synthetases, and parasite cysteine protease have all been targeted by drug-development efforts, but no compounds have advanced to clinical trials.
Inflammation potentiates miR-939 expression and packaging into small extracellular vesicles
Published in Journal of Extracellular Vesicles, 2019
Sujay Ramanathan, Botros B. Shenoda, Zhucheng Lin, Guillermo M. Alexander, Arthur Huppert, Ahmet Sacan, Seena K. Ajit
The functional effects of an sEV cargo can be determined by manipulating the source and hence its content. We sought to obtain sEVs derived from THP-1 cells overexpressing and conversely knocked out for miR-939. In humans, miR-939 is located on the long arm of chromosome 8, at the exon-intron junction of the cleavage and polyadenylation specificity factor subunit 1 (CPSF1). CPSF1 is part of the large protein complex essential for processing mRNA precursors. Hence, we did not pursue a gene knockout for miR-939 due to the anticipated perturbation of this essential gene and deleterious consequences on cell survival. As an alternative, we incubated recipient THP-1 cells with sEVs electroporated either with miR-939 or anti-miR-939 for 24 h and performed a global gene expression analysis using RNA-sequencing. We observed that several inflammatory genes are differentially expressed in THP-1 cells upon incubation with control sEVs as we had previously observed (See Figure 4), with most of these genes upregulated indicating a heightened inflammatory response (Figure 8). Anti-miR-939 treated sEVs display a similar transcriptional profile as control sEVs. Incubation with miR-939 electroporated sEVs reverses, albeit not completely, the inflammatory state compared to control sEVs, bringing the transcriptional profile of inflammatory genes closer to naïve state. Complete data is shown in Supplementary Table 1. This supports a protective role of miR-939 in attenuating inflammation.
Benzoxaborole compounds for therapeutic uses: a patent review (2010- 2018)
Published in Expert Opinion on Therapeutic Patents, 2018
Alessio Nocentini, Claudiu T. Supuran, Jean-Yves Winum
Further inhibition against Plasmodium falciparum can be achieved by introducing a single fluorine atom at the 4, 5, or 6 position of AN3661 (18–20, Figure 13) [77]. Sonoiki et al. recently identified in the parasite whole-genome sequence that mutations in the gene pfcpsf3 occurred in every AN3661-resistant parasite line [78]. This gene encodes for a homologue of subunit 3 of the cleavage and polyadenylation specificity factor (CPSF) complex, which has been well characterized in various eukaryotes. Dockings performed on a model of the PfCPSF3, built based on the crystal structure of T. thermophilus TTHA0252 (PDB code: 3IEM), were consistent with the structure-activity relationships established for the AN3661 series of compounds as antimalarial agents. The oxaborole group is essential for activity, because replacement of a carbon atom for the boron is detrimental for the activity. The carboxylic acid group is important for activity, although it can be switched to other acidic groups such as a tetrazole. The negatively charged tetrahedral oxab orole group acts as a unique ion chelator engaging the two zinc ions at the active site [78]. The bi-metallic chelation of AN3661 in the active site of PfCPSF3 is consistent with what observed for other benzoxaboroles, which have been demonstrated to bind to bi-metal centers.