Interferons as Therapeutic Agents for Infectious Diseases

Bergman, Scott; Ferguson, McKenzie C; Santanello, Cathy

doi:10.1016/j.idc.2011.07.008

Cited by 27 publications

(20 citation statements)

References 88 publications

(105 reference statements)

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“…However, experience with combination therapies is still limited, and the potential of producing viral escape mutants cannot be ruled out. An alternative, albeit less specific antiviral therapy is interferon (IFN) which, however, is only effective against a limited number of viral pathogens [15]. Moreover, because IFN treatment is prohibitively expensive and burdened with adverse side-effects, the therapy often results in low patient compliance [16,17].…”

Section: Introductionmentioning

confidence: 99%

Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry

et al. 2013

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BackgroundWe previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry.ResultsExtensive analysis of the tannins’ mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses.ConclusionsCHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified.

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Section: Introductionmentioning

confidence: 99%

Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry

et al. 2013

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“…Currently, two native and two PEGylated interferon α products exist in the pharmaceutical market [7]. Interferon α-2 products, such as interferon α-2a (IFNA2) are used to treat multiple diseases such as hairy cell leukemia and hepatitis c [4, 8–10].…”

Section: Introductionmentioning

confidence: 99%

High yield soluble bacterial expression and streamlined purification of recombinant human interferon α-2a

Bis

Stauffer

Singh

et al. 2014

Protein Expression and Purification

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Interferon α-2a (IFNA2) is a member of the Type I interferon cytokine family, known for its antiviral and anti-proliferative functions. The role of this family in the innate immune response makes it an attractive candidate for the treatment of many viral and chronic immune-compromised diseases. Recombinant IFNA2 is clinically used to modulate hairy cell leukemia as well as hepatitis c. Historically, IFNA2 has been purified from human leukocytes as well as bacterial expression systems. In most cases, bacterial expression of IFNA2 resulted in inclusion body formation, or required numerous purification steps that decreased the protein yield. Here, we describe an expression and purification scheme for IFNA2 using a pET-SUMO bacterial expression system and a single purification step. Using SUMO protein as the fusion tag achieved high soluble protein expression. The SUMO tag was cleaved with the Ulp1 protease leaving no additional amino acids on the fusion terminus following the cleavage. Mass spectrometry, circular dichroism, 2D heteronuclear NMR, and analytical ultracentrifugation confirmed the amino acid sequence identity, secondary and tertiary protein structures, and the solution behavior of the purified IFNA2. The purified protein also has antiviral and anti-proliferative activities comparable to the WHO International Standard, NIBSC 95/650, and the IFNA2 standard available from PBL Assay Science. Combining the expression and purification protocols developed here to produce IFNA2 on a laboratory scale with the commercial fermenter technology commonly used in pharmaceutical industry may further enhance IFNA2 yields, which will promote the development of interferon-based protein drugs to treat various disorders.

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“…Current therapeutic regimens for the therapy of hepatitis C and hepatitis B include parenteral IFN-α. 36 Clinical trials of TLR7 agonists for hematological malignancies are also currently underway. 37 The currently known small molecule agonists of TLR7 occupy a very small chemical space, and are represented by the 1H-imidazo [4,5-c]quinolines, 38 8-hydroxy- [39][40][41] or 8-oxoadenines, 42 and guanine nucleoside analogues.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines

et al. 2013

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Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of IFN-α/β which plays essential functions in the control of adaptive immunity. We had previously examined structure-activity relationships (SAR) in TLR7/8-agonistic imidazoquinolines with a focus on substituents at the N(1), C(2), N(3) and N(4) positions, and we now report SAR on 1H-imidazo[4,5-c]pyridines. 1-Benzyl-2-butyl-1H-imidazo[4,5-c]pyridin-4-amine was found to be a pure TLR7-agonist with negligible activity on TLR8. Increase in potency was observed in N(6)-substituted analogues, especially in those compounds with electron-rich substituents. Direct aryl-aryl connections at C6 abrogated activity, but TLR7 agonism was reinstated in 6-benzyl and 6-phenethyl analogues. Consistent with the pure TLR7-agonistic behavior, prominent IFN-α induction in human PBMCs was observed with minimal proinflammatory cytokine induction. A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine. Distinct differences in N(6)-substituted analogues were observed with respect to IFN-α induction in human PBMCs on the one hand, and CD69 upregulation in lymphocytic subsets, on the other.

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Interferons as Therapeutic Agents for Infectious Diseases

Cited by 27 publications

References 88 publications

Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry

Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry

High yield soluble bacterial expression and streamlined purification of recombinant human interferon α-2a

Structure–activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines

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