Browsing by Subject "Antiviral"

Now showing 1 - 6 of 6
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    A Novel Regioselective Approach to Cyclize Phage-Displayed Peptides in Combination with Epitope-Directed Selection to Identify a Potent Neutralizing Macrocyclic Peptide for SARS-CoV-2
    (American Chemical Society, 2022) Hampton, J. Trae; Lalonde, Tyler J.; Tharp, Jeffery M.; Kurra, Yadagiri; Alugubelli, Yugendar R.; Roundy, Christopher M.; Hamer, Gabriel L.; Xu, Shiqing; Liu, Wenshe Ray; Biochemistry and Molecular Biology, School of Medicine
    Using the regioselective cyanobenzothiazole condensation reaction with an N-terminal cysteine and the chloroacetamide reaction with an internal cysteine, a phage-displayed macrocyclic 12-mer peptide library was constructed and subsequently validated. Using this library in combination with iterative selections against two epitopes from the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, macrocyclic peptides that strongly inhibit the interaction between the Spike RBD and ACE2, the human host receptor of SARS-CoV-2, were identified. The two epitopes were used instead of the Spike RBD to avoid selection of nonproductive macrocyclic peptides that bind RBD but do not directly inhibit its interactions with ACE2. Antiviral tests against SARS-CoV-2 showed that one macrocyclic peptide is highly potent against viral reproduction in Vero E6 cells with an EC50 value of 3.1 μM. The AlphaLISA-detected IC50 value for this macrocyclic peptide was 0.3 μM. The current study demonstrates that two kinetically-controlled reactions toward N-terminal and internal cysteines, respectively, are highly effective in the construction of phage-displayed macrocyclic peptides, and the selection based on the SARS-CoV-2 Spike epitopes is a promising methodology in the identification of peptidyl antivirals.
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    Design and testing of Hepatitis Delta Ribozymes for suppression of Chikungunya virus infection in cell cultures
    (European Society of Medicine, 2024) Fraser, Mark E.; Kucharski, Cheryl; Loh, Zoe; Hanahoe, Erin; Fraser, Malcolm J., Jr.; Medicine, School of Medicine
    Chikungunya virus is an emerging pathogen with widespread distribution in regions of Africa, India, and Asia that threatens to spread into temperate climates following the introduction of its major vector, Aedes albopictus. Recent cases have been documented in Europe, the Caribbean, and the Americas. Chikungunya virus causes a disease frequently misdiagnosed as Dengue fever, with potentially life-threatening symptoms that can result in long term debilitating arthritis. There have been ongoing investigations of possible therapeutic interventions for both acute and chronic symptoms, but to date none have proven effective in reducing the severity or lasting effects of this disease. Recently, a promising vaccine candidate has received accelerated approval, indicating the importance of remedies to this emerging worldwide health threat. Nonetheless, therapeutic interventions for Chikungunya and other mosquito borne virus diseases are urgently needed yet remain elusive. The increasing risk of spread from endemic regions via human travel and commerce, coupled with the absence of a vaccine or approved therapeutic, puts a significant proportion of the world population at risk for this disease. In this report we explore the possibility of using Specific On/oFf Adapter Hepatitis Delta Virus Ribozymes as antivirals in cells infected with Chikungunya virus. The results we obtained suggest there could be some role in using these ribozyme molecules as antiviral therapies for not only Chikungunya virus, but potentially other viruses as well.
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    From the Cochrane Library: Interventions for Pityriasis Rosea
    (JMIR, 2023-06-05) Méndez, Alejandra; Stevens, Carly; Murina, Andrea; Dermatology, School of Medicine
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    Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics.
    (Elsevier, 2015-10) Guo, Ju-Tao; Guo, Haitao; Department of Microbiology and Immunology, IU School of Medicine
    Persistent hepatitis B virus (HBV) infection relies on the stable maintenance and proper functioning of a nuclear episomal form of the viral genome called covalently closed circular (ccc) DNA. One of the major reasons for the failure of currently available antiviral therapeutics to achieve a cure of chronic HBV infection is their inability to eradicate or inactivate cccDNA. In this review article, we summarize our current understanding of cccDNA metabolism in hepatocytes and the modulation of cccDNA by host pathophysiological and immunological cues. Perspectives on the future investigation of cccDNA biology, as well as strategies and progress in therapeutic elimination and/or transcriptional silencing of cccDNA through rational design and phenotypic screenings, are also discussed. This article forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”
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    The use of antivirals in the treatment of human monkeypox outbreaks: a systematic review
    (Elsevier, 2023) Shamim, Muhammad Aaqib; Padhi, Bijaya Kumar; Satapathy, Prakasini; Veeramachaneni, Sai D.; Chatterjee, Chandrima; Tripathy, Snehasish; Akhtar, Naushaba; Pradhan, Anindita; Dwivedi, Pradeep; Mohanty, Aroop; Rodriguez-Morales, Alfonso J.; Sah, Ranjit; Al-Tammemi, Ala’a B.; Al-Tawfiq, Jaffar A.; Nowrouzi-Kia, Behdin; Chattu, Vijay Kumar; Medicine, School of Medicine
    Objectives: Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant literature available on the use of antivirals in MPXV infection. This systematic review compiles all evidence of various antivirals used on their efficacy and safety and summarizes their mechanisms of action. Methods: A review was done of all original studies mentioning individual patient data on the use of antivirals in patients with MPXV infection. Results: Of the total 487 non-duplicate studies, 18 studies with 71 individuals were included. Tecovirimat was used in 61 individuals, followed by cidofovir in seven and brincidofovir (BCV) in three individuals. Topical trifluridine was used in four ophthalmic cases in addition to tecovirimat. Of the total, 59 (83.1%) were reported to have complete resolution of symptoms; one was experiencing waxing and waning of symptoms, only one (1.8%) had died, and the others were having a resolution of symptoms. The death was thought unrelated to tecovirimat. Elevated hepatic panels were reported among all individuals treated with BCV (leading to treatment discontinuation) and five treated with tecovirimat. Conclusion: Tecovirimat is the most used and has proven beneficial in several aggravating cases. No major safety concerns were detected upon its use. Topical trifluridine was used as an adjuvant treatment option along with tecovirimat. BCV and cidofovir were seldom used, with the latter often being used due to the unavailability of tecovirimat. BCV was associated with treatment discontinuation due to adverse events.
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    Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters
    (MDPI AG (Basel, Switzerland), 2015-03-23) Toth, Karoly; Ying, Baoling; Tollefson, Ann E.; Spencer, Jacqueline; Balakrishnan, Lata; Sagartz, John E.; Buller, Robert Mark; Wold, William S.M.; Department of Biology, School of Science
    Adenovirus infections of immunocompromised pediatric hematopoietic stem cell transplant patients can develop into serious and often deadly multi-organ disease. There are no drugs approved for adenovirus infections. Cidofovir (an analog of 2-deoxycytidine monophosphate) is used at times but it can be nephrotoxic and its efficacy has not been proven in clinical trials. Brincidofovir, a promising lipid-linked derivative of cidofovir, is in clinical trials. Ganciclovir, an analog of 2-deoxyguanosine, has been employed occasionally but with unknown efficacy in the clinic. In this study, we evaluated valganciclovir against disseminated adenovirus type 5 (Ad5) infection in our permissive immunosuppressed Syrian hamster model. We administered valganciclovir prophylactically, beginning 12 h pre-infection or therapeutically starting at Day 1, 2, 3, or 4 post-infection. Valganciclovir significantly increased survival, reduced viral replication in the liver, and mitigated the pathology associated with Ad5 infection. In cultured cells, valganciclovir inhibited Ad5 DNA replication and blocked the transition from early to late stage of infection. Valganciclovir directly inhibited Ad5 DNA polymerase in vitro, which may explain, at least in part, its mechanism of action. Ganciclovir and valganciclovir are approved to treat infections by certain herpesviruses. Our results support the use of valganciclovir to treat disseminated adenovirus infections in immunosuppressed patients.