Clinical evidence of an interferon-glucocorticoid therapeutic synergy in COVID-19.

Synthetic glucocorticoid dexamethasone is the first trial-proven drug that reduces COVID-19 mortality by suppressing immune system. In contrast, interferons are a crucial component of host antiviral immunity and can be directly suppressed by glucocorticoids. To investigate whether therapeutic interferons can compensate glucocorticoids-induced loss of antiviral immunity, we retrospectively analyzed a cohort of 387 PCR-confirmed COVID-19 patients with quasi-random exposure to interferons and conditional exposure to glucocorticoids. Among patients receiving glucocorticoids, early interferon therapy was associated with earlier hospital discharge (adjusted HR 1.68, 95% CI 1.19-2.37) and symptom relief (adjusted HR 1.48, 95% CI 1.06-2.08), while these associations were insignificant among glucocorticoids nonusers. Early interferon therapy was also associated with lower prevalence of prolonged viral shedding (adjusted OR 0.24, 95% CI 0.10-0.57) only among glucocorticoids users. Additionally, these associations were glucocorticoid cumulative dose- and timing-dependent. These findings reveal potential therapeutic synergy between interferons and glucocorticoids in COVID-19 that warrants further investigation.

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity.

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.

Lactoferrin as potential preventative and adjunct treatment for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is rapidly advancing across the globe despite drastic public and personal health measures. Antivirals and nutritional supplements have been proposed as potentially useful against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes COVID-19, but few have been clinically established. Lactoferrin (Lf) is a naturally occurring, non-toxic glycoprotein that is orally available as a nutritional supplement and has established in vitro antiviral efficacy against a wide range of viruses, including SARS-CoV, a closely related coronavirus to SARS-CoV-2. Furthermore, Lf possesses unique immunomodulatory and anti-inflammatory effects that may be especially relevant to the pathophysiology of severe COVID-19 cases. Here we review the underlying biological mechanisms of Lf as an antiviral and immune regulator, and propose its unique potential as a preventative and adjunct treatment for COVID-19. We hope that further research and development of Lf nutritional supplementation would establish its role for COVID-19.

[Effects of diphenyl derivatives on electrophoretic mobility of murine T lymphocytes].

The early changes of electrophoretic mobility (EPM) of murine T lymphocytes induced by structural analogues of amixine-dihydrochloryde 4,4'-bis-[2(diethylamino)ethoxy]diphenyl (compound 1) and dihydrochloryde 2-methoxycarbonil-4,4'-bis-[2(diethylamino)ethoxy]diphenyl (compound 2) were studied by electrophoresis technique. During the interval 0-2 hours all compounds increased the absolute values of EPM in comparison with control. These changes were of the same kind--distinctions were quantitative. Amixine and compound 1 during the interval 2-4 hours additionally increased the EPM. The compound 2, on the contrary, decreased the EPM. It was shown that the opposite effects of the aforementioned compounds were caused by the fact that amixine and compound 1 induce, and compound 2 does not induce IFN production in T lymphocytes in vitro. The results of our experiments are important for understanding of the mechanisms of immunomodulating effect of amixine and its structural analogues.

Discovery of a highly potent series of TLR7 agonists.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.

The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans.

BACKGROUND: Respiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the host's interferon- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics. METHODS: Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children. RESULTS: At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene. CONCLUSIONS: Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.

Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: discovery of 8-mercaptoadenines as potent interferon-inducers.

Recently, we have identified 9-benzyl-8-hydroxyadenines bearing an appropriate substituent (a butoxy, propylthio or butylamino group) at the 2-position as potent interferon (IFN)-inducers. Herein we report the design, synthesis, and IFN-inducing activity of 8-substituted 9-benzyladenines possessing such an appropriate substituent at the 2-position. Introduction of the appropriate substituent into the 2-position of the adenine nucleus gave rise to expression of the activity even in 9-benzyladenines bearing no hydroxyl group at the 8-position. An amino group at the 6-position and a hydroxyl or thiol group carrying an acidic proton at the 8-position are required to express excellent IFN-inducing activity. 9-Benzyl-2-butoxy-8-mercaptoadenine (9) indicated the most potent activity with MEC of 0.001 microM.

[Some aspects of interferon formation in white mice]. / Nekotorye aspekty interferonoobrazovaniia v organizme belykh myshei.

White mice weighing 14-16 g were intranasally infected with LD50 of influenza virus (A/Aichi/2/68 strain). High levels both of virus and interferon were detected in the lung. Sufficient virus accumulation in the nasal cavity occurred with low interferon induction. At the same time high blood interferon levels corresponded to sporadic low viremia. Intraperitoneal injection of the interferon inducer ridostin (a pharmacological formulation of dsRNA) to BALB/c mice (18-20 g) in a dose of 5 mg/kg induced intensive blood accumulation of interferon with its peak at 8 hours postadministration (2560 U/0.2 ml), but interferon was not detected in the respiratory tract and brain of these mice. Intranasal (15 mg/kg) and aerogenic (0.4-0.6 mg/kg) administration of ridostin induced interferon mainly in the upper respiratory tract and lung. The regularities found are in agreement with the data on interferon induction by other dsRNA preparations, which makes it necessary to design dosage forms of interferon inducers for respiratory application in influenza.

Modulation by polymyxin B of the effects of interferon on human myelogenous leukemia cells.

Natural and recombinant human interferon-alpha (IFN-alpha) and -gamma (IFN-gamma) exert differentiation-inducing and cytocidal effects in vitro on cells of the human myeloblastic leukemia cell line ML-2. These activities of IFNs are modulated by polymyxin B (PMB), a cyclic polycationic peptide antibiotic effective on Gram-negative bacilli. The modulating effect of PMB varies according to the species of IFN, namely, PMB enhances the activities of either natural IFN-gamma or recombinant IFN-gamma, while it inhibits the effects of either natural IFN-alpha or recombinant IFN-alpha. The cause of this variety in PMB effect on IFNs remains to be clarified.