Improved antiviral activity of a polyamide against high-risk human papillomavirus via N-terminal guanidinium substitution

Castañeda, Carlos H.; Scuderi, M. José; Edwards, Terri G.; Harris, George D.; Dupureur, Cynthia M.; Koeller, Kevin J.; Fisher, Chris; Bashkin, James K.

doi:10.1039/c6md00371k

Cited by 8 publications

(5 citation statements)

References 54 publications

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“…They found that presence of N-terminal guanidinium results in improved antiviral activity. 64 This group also studied the interactions of these antiviral polyamides with DNA. 65 Previously, they had reported a series of large hairpin polyamides (with 10 or more rings) with low IC 50 values against HPV and no detectable toxicity.…”

Section: Polyamides Derivativesmentioning

confidence: 99%

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Recent developments in compounds acting in the DNA minor groove

2019

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Section: Polyamides Derivativesmentioning

confidence: 99%

“…57,68,69 Bashkin and collaborators hypothesise that even though HBs will be established in the DNA minor groove, the cumulative effect of many hundreds of rigid, crescent polyamides binding to supercoiled DNA is more important for the antiviral activity observed. 64…”

Section: Polyamides Derivativesmentioning

confidence: 99%

Recent developments in compounds acting in the DNA minor groove

2019

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“…One such class of drugs that have been shown to target nucleotide moieties are polyamides. Several polyamides have been developed as inhibitors of gene expression and other biological effectors that bind double-stranded DNA in a sequence-specific manner (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), and other polyamides have also been developed as broad-spectrum antivirals for papillomaviruses and polyomaviruses precisely because they do not show sequence-specific binding properties (19)(20)(21)(22)(23)(24)(25); J. K. Bashkin et al, unpublished data). Others have also since discovered nonspecific polyamide effects (26,27).…”

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confidence: 99%

A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

Gumpper

Castañeda

et al. 2018

J Virol

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Polyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide-treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar in all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus. Negative-strand RNA viruses (NSVs) include several life-threatening pathogens, such as rabies virus, respiratory syncytial virus, and Ebola virus. There are no effective antiviral drugs against these viruses. Polyamides offer an exceptional opportunity because they may be optimized to target each NSV. Our studies on vesicular stomatitis virus, an NSV, demonstrated that a polyamide molecule could specifically target the viral RNA in the nucleocapsid and inhibit viral growth. The target specificity of the polyamide molecule was proved by its inhibition of thermo-release and RNA nuclease digestion of the RNA bound in a model nucleocapsid, and a crystal structure of the polyamide inside the nucleocapsid. This encouraging observation provided the proof-of-concept rationale for designing polyamides as antiviral drugs against NSVs.

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“…This targeted approach holds great potential for developing effective and safe treatments for viral diseases, including emerging and drug‐resistant viruses. Antisense oligos, siRNAs, and RNA vaccines have been tested successfully as antiviral reagents, and PIPs have joined this club with molecules tested against polyoma and papilloma viruses 114–116 . Furthermore, treating inherited genetic diseases, certain cancers, and viral diseases using nucleic acid‐based small‐molecule drugs to control transcription factors' activity offers tremendous therapeutic potential and is an exciting frontier for drug design and discovery.…”

Section: Discussionmentioning

confidence: 99%

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

Bai,

Ziadlou,

Vaijayanthi

et al. 2023

Allergy

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Transcription therapy is an emerging approach that centers on identifying the factors associated with the malfunctioning gene transcription machinery that causes diseases and controlling them with designer agents. Until now, the primary research focus in therapeutic gene modulation has been on small‐molecule drugs that target epigenetic enzymes and critical signaling pathways. However, nucleic acid‐based small molecules have gained popularity in recent years for their amenability to be pre‐designed and realize operative control over the dynamic transcription machinery that governs how the immune system responds to diseases. Pyrrole–imidazole polyamides (PIPs) are well‐established DNA‐based small‐molecule gene regulators that overcome the limitations of their conventional counterparts owing to their sequence‐targeted specificity, versatile regulatory efficiency, and biocompatibility. Here, we emphasize the rational design of PIPs, their functional mechanisms, and their potential as targeted transcription therapeutics for disease treatment by regulating the immune response. Furthermore, we also discuss the challenges and foresight of this approach in personalized immunotherapy in precision medicine.

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Improved antiviral activity of a polyamide against high-risk human papillomavirus via N-terminal guanidinium substitution

Cited by 8 publications

References 54 publications

Recent developments in compounds acting in the DNA minor groove

Recent developments in compounds acting in the DNA minor groove

A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

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