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Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activatorof transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), mitogen activated kinase (MAPK) andNLR family pyrin domain containing 3 (NLRP3). We have developed cellpenetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cellsand inmacrophage cell lines.SOCS-KIRpeptides exhibited antiinflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectorsandreducedclinicalsymptomsinmousemodel of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma. [ABSTRACT FROM AUTHOR]

The field of antiviral therapeutics is fixated on COVID19 and rightly so as the fatalities at the height of the pandemic in the United States were almost 1,000,000 in a twelve month period spanning parts of 2020/2021. A coronavirus called SARS-CoV2 is the causative virus. Development of a vaccine through molecular biology approaches with mRNA as the inducer of virus spike protein has played a major role in driving down mortality and morbidity. Antivirals have been of marginal value in established infections at the level of hospitalization. Thus, the current focus is on early symptomatic infection of about the first five days. The Pfizer drug paxlovid which is composed of nirmatrelvir, a peptidomimetic protease inhibitor of SARS-CoV2 Mpro enzyme, and ritonavir to retard degradation of nirmatrelvir, is the current FDA recommended treatment of early COVID19. There is no evidence of broad antiviral activity of paxlovid against other diverse viruses such as the influenza virus, poxviruses, as well as a host of respiratory viruses. Although type I interferons (IFNs) are effective against SARS-CoV2 in cell cultures and in early COVID19 infections, they have not been broadly recommended as therapeutics for COVID19. We have developed stable peptidomimetics of both types I and II IFNs based on our noncanonical model of IFN signaling involving the C-terminus of the IFNs. We have also identified two members of intracellular checkpoint inhibitors called suppressors of cytokine signaling (SOCS), SOCS1 and SOCS3 (SOCS1/3), and shown that they are virus induced intrinsic virulence proteins with activity against IFN signaling enzymes JAK2 and TYK2. We developed a peptidomimetic antagonist, based on JAK2 activation loop, against SOCS1/3 and showed that it synergizes with the IFN mimetics for potent broad spectrum antiviral activity without the toxicity of intact IFN molecules. IFN mimetics and the SOCS1/3 antagonist should have an advantage over currently used antivirals in terms of safety and potency against a broad spectrum of viruses. [ABSTRACT FROM AUTHOR]

Five representative nuclear localizing ligands for which there is documentation of translocation into the cytosol and nucleus through well-characterized pathways is reviewed, in addition to a role in gene activation by ligand/receptor in the nucleus. Interaction of ligands such as epidermal growth factor and interferon-gamma with the extracellular domains of their plasma membrane receptor results in internalization followed by translocation into the nucleus of the ligand.

Toxicity analyses have shown that interferon tau (IFN tau) and IFN alpha A have different cytotoxic effects in cells. Aside from being less toxic, IFN tau also has a different mechanism for recognizing the type I IFN receptor. Direct binding studies revealed that IFN alpha A has a higher binding affinity and is more effective in competitive binding against IFN tau to the receptor in Madin-Darby bovine kidney cells. It is suggested that the differential recognition of the receptor is responsible for the differences in the cytotoxic effects of the two interferons.

The pretreatment of mice with the non-V(sub beta)-8-specific superantigen, staphylococcal enterotoxin A (SEA) prevents the occurrence of allergic encephalomyelitis (EAE) in PL/J mice even after a second dose of V(sub beta)-8-specific superantigen, staphylococcal enterotoxin B (SEB). However treatment with SEA induces EAE at an accelerated rate in these mice. The re-activation of EaE in these mice is by the removal of the V(sub beta)-8+ T cells. Although SEA does not protect the mice from EAE, SEB is unable to re-activate EAE in SEA-pretreated mice.

A study was conducted to understand the solution structure of mouse interferon (Mu IFN gamma) and the N-terminal receptor binding domain of the protein. In the structure of MuIFN gamma, the monomeric unit in dimeric protein is characterized by 6 helices and has 35% sequence homology in relation to human and rabbit sequences. There is no stable structure in the loop joining helices A and B. The gamma region undergoes changes when associated with receptor IFN. The N-terminal receptor binding domain of the protein undergoes structural changes which provide insights into the structural basis for activation of the receptor of IFN gamma.

The staphylococcal enterotoxins (SEs) are classified as superantigens due to their potent stimulation of the immune system resulting in T cell activation and prodigious cytokine production and toxicity. This study examined the ability of superantigens to induce prophylactic antiviral activity in vivo and in vitro and evaluated potential superantigen mimetic peptides. Prophylactic treatment of mice in vivo with intraperitoneal injections of SE superantigens SEA and SEB (both at 20 μg/day for 3 days) prevented encephalomyocarditis virus (EMCV)-induced lethality in 100% and 80% of mice, respectively, as compared with control saline-treated groups in which EMCV was lethal to all mice. Furthermore, SEA (2 μg/mL) and SEB (1 μg/mL) induced antiviral activity in mouse splenocytes to produce an antiviral factor since their supernatant prevented EMCV lysis of L929 cells in tissue culture. It was found that superantigens do not directly prevent EMCV infection, but rather indirectly through inducing interferon gamma (IFNγ) production in cells as the antiviral factor. Evaluation of various superantigen mimetic peptides showed that one peptide (SEA3) had superantigen-like activity by inducing IFNγ production in cells but without the cellular proliferation, as associated with superantigens. However, the induction of IFNγ activation by the SEA3 peptide was not as pronounced, and took a much higher peptide concentration, when compared with the parent superantigen. If the negative side effects of superantigens can be eliminated, their beneficial properties can be harnessed for prophylactic treatment of viral infections and other pathologies requiring a robust immune response. [ABSTRACT FROM AUTHOR]