ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2

Chono, Koji; Katsumata, Kiyomitsu; Kontani, Toru; Kobayashi, Masayuki; Sudo, Kenji; Yokota, Tomoyuki; Konno, Kenji; Shimizu, Yoshiyuki; Suzuki, Hiroshi

doi:10.1093/jac/dkq198

Cited by 133 publications

(118 citation statements)

References 31 publications

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“…Alternatively, equation 2 could be used to yield a value for K D as previously described (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)53):…”

Section: Methodsmentioning

confidence: 99%

“…As a result, helicases are key players in a wide variety of DNA and RNA metabolic processes, such as recombination, chromatin remodeling, and DNA transport (4)(5)(6). Most recently, helicases have emerged as potential therapeutic targets for diseases ranging from cancer to Gram-positive bacterial infections (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Classified into six superfamilies, superfamily 1 and 2 (SF1 and SF2) helicases are the most similar, sharing up to seven conserved sequence motifs and core RecA-like folds (1)(2)(3).…”

mentioning

confidence: 99%

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Unique Helicase Determinants in the Essential Conjugative TraI Factor from Salmonella enterica Serovar Typhimurium Plasmid pCU1

2014

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The widespread development of multidrug-resistant bacteria is a major health emergency. Conjugative DNA plasmids, which harbor a wide range of antibiotic resistance genes, also encode the protein factors necessary to orchestrate the propagation of plasmid DNA between bacterial cells through conjugative transfer. Successful conjugative DNA transfer depends on key catalytic components to nick one strand of the duplex DNA plasmid and separate the DNA strands while cell-to-cell transfer occurs. The TraI protein from the conjugative Salmonella plasmid pCU1 fulfills these key catalytic roles, as it contains both single-stranded DNA-nicking relaxase and ATP-dependent helicase domains within a single, 1,078-residue polypeptide. In this work, we unraveled the helicase determinants of Salmonella pCU1 TraI through DNA binding, ATPase, and DNA strand separation assays. TraI binds DNA substrates with high affinity in a manner influenced by nucleic acid length and the presence of a DNA hairpin structure adjacent to the nick site. TraI selectively hydrolyzes ATP, and mutations in conserved helicase motifs eliminate ATPase activity. Surprisingly, the absence of a relatively short (144-residue) domain at the extreme C terminus of the protein severely diminishes ATP-dependent strand separation. Collectively, these data define the helicase motifs of the conjugative factor TraI from Salmonella pCU1 and reveal a previously uncharacterized C-terminal functional domain that uncouples ATP hydrolysis from strand separation activity.H elicases are molecular motors that drive the separation of duplex nucleic acid strands through the coupling of ATP hydrolysis to unwinding (1-3). As a result, helicases are key players in a wide variety of DNA and RNA metabolic processes, such as recombination, chromatin remodeling, and DNA transport (4-6). Most recently, helicases have emerged as potential therapeutic targets for diseases ranging from cancer to Gram-positive bacterial infections (7-18). Classified into six superfamilies, superfamily 1 and 2 (SF1 and SF2) helicases are the most similar, sharing up to seven conserved sequence motifs and core RecA-like folds (1-3). Furthermore, SF1 helicases comprise the largest class and can be further subdivided into SF1A and SF1B, based on the direction of helicase translocation along the strand; SF1A helicases progress 3= to 5= and SF1B 5= to 3= (3). Despite their importance, SF1B helicases are still poorly characterized in comparison to SF1A and SF2 helicases, though some recent studies have expanded our knowledge (19-21). SF1B helicases are critical to a diverse range of processes, including DNA repair by human DNA helicase B (22), telomere regulation by Pif1 (23), and conjugative plasmid transfer by F TraI (24).Conjugative plasmid transfer (CPT) mediates the propagation of antibiotic resistance genes and virulence factors within commensal and pathogenic bacteria (25-27) and relies on the helicase domain of a bifunctional protein to facilitate plasmid DNA transfer (24,(28)(29)(30). Early work characteri...

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“…Alternatively, equation 2 could be used to yield a value for K D as previously described (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)53):…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Unique Helicase Determinants in the Essential Conjugative TraI Factor from Salmonella enterica Serovar Typhimurium Plasmid pCU1

2014

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“…The antiviral activities of ASP2151 and ACV against HSVs were tested using a plaque reduction assay, as described previously (6). Briefly, HEF cells were seeded into multiwell plates and incubated until they formed a monolayer.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, a new class of nonnucleoside antivirals, termed herpesvirus helicase-primase inhibitors (HPIs), has been identified (6)(7)(8). A few clinical trials with HPIs have been completed (9; http: //clinicaltrials.gov/ct2/show/NCT00487682; http://clinicaltrials .gov/ct2/show/NCT01047540; http://clinicaltrials.gov/ct2/show /NCT00486200), with the results suggesting that these drugs may offer another strategy for treating HSV and VZV infection.…”

mentioning

confidence: 99%

“…Recently, we reported the discovery of ASP2151, a novel HPI, which had potent antiviral activity against HSVs both in vitro and in vivo (6,(25)(26)(27). Here, we conducted PK, dose fractionation, and continuous-infusion studies in an HSV-1-infected murine model to define the PK and PD of ASP2151 and to analyze the correlation between PK parameters and the in vivo anti-HSV-1 activity of ASP2151.…”

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confidence: 99%

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Pharmacokinetics and Pharmacodynamics of ASP2151, a Helicase-Primase Inhibitor, in a Murine Model of Herpes Simplex Virus Infection

Katsumata

Chono

Kato

et al. 2013

Antimicrob Agents Chemother

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ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus.Here, to determine and analyze the correlation between the pharmacodynamic (PD) and pharmacokinetic (PK) parameters of ASP2151, we examined the PD profile of ASP2151 using in vitro plaque reduction assay and a murine model of HSV-1 infection. ASP2151 inhibited the in vitro replication of HSV-1 with a mean 50% effective concentration (EC 50 ) of 14 ng/ml. In the cutaneously HSV-1-infected mouse model, ASP2151 dose dependently suppressed intradermal HSV-1 growth, with the effect reaching a plateau at a dose of 30 mg/kg of body weight/day. The dose fractionation study showed that intradermal HSV-1 titers were below the detection limit in mice treated with ASP2151 at 100 mg/kg/day divided into two daily doses and at 30 or 100 mg/kg/day divided into three daily doses. The intradermal HSV-1 titer correlated with the maximum concentration of drug in serum (C max ), the area under the concentration-time curve over 24 h (AUC 24h ), and the time during which the concentration of ASP2151 in plasma was above 100 ng/ml (T >100 ). The continuous infusion of ASP2151 effectively decreased intradermal HSV-1 titers below the limit of detection in mice in which the ASP2151 concentration in plasma reached 79 to 145 ng/ml. Our findings suggest that the antiviral efficacy of ASP2151 is most closely associated with the PK parameter T >100 in HSV-1-infected mice. Based on these results, we propose that a plasma ASP2151 concentration exceeding 100 ng/ml for 21 to 24 h per day provides the maximum efficacy in HSV-1-infected mice.

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Anti‐DNA Virus Agents

Herdewijn¹,

Gu²,

Clercq³

2021

Burger's Medicinal Chemistry and Drug Discovery

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Although most of the drugs that are used to treat deoxyribonucleic acid (DNA) virus infections have been on the market for more than 10 years, anti‐DNA virus drug discovery remains an active field of research. There are still DNA viruses that are important human pathogens for which no therapy is available (i.e. adenovirus), for which the available drugs show considerable toxicity (i.e. cytomegalovirus), or for which the current drug therapy is insufficient to eradicate the virus (i.e. hepatitis B virus). In this article, we have provided an overview of the anti‐DNA virus drugs that are presently on the market together with a description of the new compounds, all active against DNA viruses, covering the literature of the past 10 years. We have focused on the structure of newly discovered compounds, and the mechanism of action and clinical data, when available. Although the major efforts are still in the nucleotide antimetabolite field, the anti‐DNA virus field of research and development has shifted recently in the direction of the study of more common heterocyclic structures as protein inhibitors.

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ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2

Abstract: ASP2151 is a novel herpes helicase-primase inhibitor that warrants further investigation for the potential treatment of both VZV and HSV infections.

Cited by 133 publications

References 31 publications

Unique Helicase Determinants in the Essential Conjugative TraI Factor from Salmonella enterica Serovar Typhimurium Plasmid pCU1

Unique Helicase Determinants in the Essential Conjugative TraI Factor from Salmonella enterica Serovar Typhimurium Plasmid pCU1

Pharmacokinetics and Pharmacodynamics of ASP2151, a Helicase-Primase Inhibitor, in a Murine Model of Herpes Simplex Virus Infection

Anti‐DNA Virus Agents

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