The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of smallpox disease

Trost, Lawrence C.; Rose, Michelle; Khouri, Jody; Keilholz, Laurie; Long, James P.; Godin, Stephen; Foster, Scott A.

doi:10.1016/j.antiviral.2015.02.007

Cited by 48 publications

(36 citation statements)

References 15 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the first effective drugs in clinical use as a parenteral treatment in severe OPV infections was cidofovir, a bisphosphonate developed at REGA, in Belgium [31,35]) and FDA approved against human cytomegalovirus (HCMV). The ether lipid analogue brincidofovir (CMX001), a prodrug of cidofovir, has shown efficacy in small animal models and is awaiting FDA approval [26,44,56,115,116,118,139]. The F13L virus egress inhibitor tecovirimat (ST-246, TPOXX®) has been independently developed to treat smallpox infections and has been FDA approved since 2018.…”

Section: Poxviridaementioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

View full text Add to dashboard Cite

The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

show abstract

Section: Poxviridaementioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

View full text Add to dashboard Cite

show abstract

“…2) is an oral antiviral drug candidate for treating smallpox infections. It has a lipid moiety masking the phosphate group, is taken up well by cells, has low toxicity, and is active against a wide range of DNA viruses in animals, including poxviruses, adenoviruses, herpesviruses, and CMV (Trost et al 2015;Cundy et al 1999). Interestingly, it has been shown using vaccinia virus DNA polymerase, that though Cid-DP is incorporated into DNA in the polymerase reaction, the process is relatively inefficient, and termination of synthesis occurs after extension by an additional nucleotide, a delayed termination similar to that shown for Remdesivir for RdRp; in the penultimate position, the incorporated Cidofovir is not removed by 3'-exonuclease activity and resistance is not common for Cidofovir (Magee et al 2005).…”

Section: Selection Of Candidate Nucleoside Triphosphates For Coronavimentioning

confidence: 99%

A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19

Jockusch

Tao

et al. 2020

Preprint

View full text Add to dashboard Cite

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNAdependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of additional nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2' or 3' modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses' exonuclease activity. We examined these nucleotide analogues with regard to their ability to be incorporated by the RdRps in the polymerase reaction and then prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (Carbovir triphosphate, Ganciclovir triphosphate, Stavudine triphosphate, Entecavir triphosphate, 3'-O-methyl UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2'-O-methyl UTP), and 3 did not terminate the polymerase reaction (2'-fluoro-dUTP, 2'-amino-dUTP and Desthiobiotin-16-UTP). The coronavirus genomes encode an exonuclease that apparently requires a 2'-OH group to excise mismatched bases at the 3'-terminus. In this study, all of the nucleoside triphosphate analogues we evaluated form Watson-Cricklike base pairs. All the nucleotide analogues which demonstrated termination either lack a 2'-OH, have a blocked 2'-OH, or show delayed termination. These nucleotides may thus have the potential to resist exonuclease activity, a property that we will investigate in the future. Furthermore, prodrugs of five of these nucleotide analogues (Brincidofovir/Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA approved for other viral infections, and their safety profile is well known. Thus, they can be evaluated rapidly as potential therapies for COVID-19.

show abstract

“…In vitro studies of brincidofovir report significant activity (~100‐fold more potent than cidofovir) against multiple variola virus strains . In animal models of smallpox disease, brincidofovir demonstrated a dose‐dependent increase in survival . Tecovirimat (previously ST‐246) is another oral drug under investigation as a potential treatment of smallpox.…”

Section: Biological Threatsmentioning

confidence: 99%

“…68 In animal models of smallpox disease, brincidofovir demonstrated a dose-dependent increase in survival. 69 Tecovirimat (previously ST-246) is another oral drug under investigation as a potential treatment of smallpox. In an animal study of nonhuman primates infected with variola virus, 50% of controls given placebo died, whereas 100% of animals treated with tecovirimat survived regardless of drug administration pre-or postlesion appearance.…”

Section: Botulismmentioning

confidence: 99%

Disaster Preparedness: Biological Threats and Treatment Options

et al. 2018

View full text Add to dashboard Cite

Biological disasters can be natural, accidental, or intentional. Biological threats have made a lasting impact on civilization. This review focuses on agents of clinical significance, bioterrorism, and national security, specifically Category A agents (anthrax, botulism, plague, tularemia, and smallpox), as well as briefly discusses other naturally emerging infections of public health significance, Ebola virus (also a Category A agent) and Zika virus. The role of pharmacists in disaster preparedness and disaster response is multifaceted and important. Their expertise includes clinical knowledge, which can aid in drug information consultation, patient-specific treatment decision making, and development of local treatment plans. To fulfill this role, pharmacists must have a comprehensive understanding of medical countermeasures for these significant biological threats across all health care settings. New and reemerging infectious disease threats will continue to challenge the world. Pharmacists will be at the forefront of preparedness and response, sharing knowledge and clinical expertise with responders, official decision makers, and the general public.

show abstract

The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of smallpox disease

Cited by 48 publications

References 15 publications

Antivirals in medical biodefense

Antivirals in medical biodefense

A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19

Disaster Preparedness: Biological Threats and Treatment Options

Contact Info

Product

Resources

About