galidesivir and Hemorrhagic-Fever--Ebola

Ebola virus (EBOV) was discovered for the first time in 1976. It belongs to the family Filoviridae, which causes hemorrhagic fever that could lead to death in a few days. West Africa faced a major outbreak where symptoms appeared in the form of chills, myalgia, fever, diarrhea, and vomiting, and the disease finally reached a severe state as a result of hemorrhagic complications and failure of multiple organs. EBOV spreads by contact with body fluids of an infected person such as blood, saliva, urine, and seminal fluid, and also spreads by a contact with contaminated surfaces. Viral infection depends on the virus and host defenses. When the virus invades the body, the immune system becomes activated in an attempt to neutralize it. However, if this fails, EBOV viral infection spreads and leads to impaired innate and adaptive immune responses and uncontrollable viral replication. Consequently, the symptomatic patient is isolated and various medicinal regimens such as BCX-4430n TKM- EBOV are used, to cure EBOV, though, a specific treatment is not available. Accordingly, the aim of the present review is to survey and summarize the recent literature pertaining to the outbreak of EBOV, systematic infection of the human body, along with transmission and treatment. In addition, the review also aims to identify areas that need more research and development in combatting this dangerous virus. In the meantime, it should be noted that there is no fully FDA approved drug to treat infections by this virus. Therefore, there is a pressing need to focus on drug discovery along with public awareness to effectively manage any outbreaks in the future.

Topics: Adenine; Adenosine; Africa, Western; Animals; Antiviral Agents; Disease Outbreaks; Drug Discovery; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Immune System; Purine Nucleosides; Pyrrolidines; Virus Replication

Despite the unprecedented Ebola virus outbreak response in West Africa, no Ebola medical countermeasures have been approved by the US Food and Drug Administration. However, multiple valuable lessons have been learned about the conduct of clinical research in a resource-poor, high risk-pathogen setting. Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acid-based drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp). We review Ebola therapeutics progress in the aftermath of the West Africa Ebola virus outbreak and attempt to offer a glimpse of a path forward.

Topics: Adenine; Adenosine; Adenosine Monophosphate; Africa, Western; Alanine; Animals; Antiviral Agents; Disease Outbreaks; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Purine Nucleosides; Pyrrolidines; Ribonucleotides

The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations.

Topics: Adenine; Adenosine; Amides; Animals; Antiviral Agents; Disease Outbreaks; Ebolavirus; Healthy Volunteers; Hemorrhagic Fever, Ebola; Humans; Models, Animal; Purine Nucleosides; Pyrazines; Pyrrolidines

The current Ebola virus outbreak is unprecedented in its scope and international impact. Given that there are currently no approved antivirals to treat Ebola virus, there is urgency to conduct more rapid development and evaluation of Ebola antivirals. Recently, the World Health Organization identified a number of antivirals as high priority to include AVI-6002 (AVI-7537 and AVI-7539), BCX4430, brincidofovir, favipiravir, and TKM-100802. This review describes these chemically synthesized inhibitors of Ebola virus, relevant patent development and gives an update on their current status.

Topics: Adenine; Adenosine; Amides; Antiviral Agents; Cytosine; Drug Discovery; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Organophosphonates; Patents as Topic; Purine Nucleosides; Pyrazines; Pyrrolidines

Topics: Adenine; Adenosine; Antiviral Agents; Benzamides; Chloroquine; Communicable Diseases, Emerging; Cyclosporins; Cytosine; Dengue; Drug Approval; Drug Design; Erlotinib Hydrochloride; Hemorrhagic Fever, Ebola; Humans; Imatinib Mesylate; Indoles; Organophosphonates; Piperazines; Purine Nucleosides; Pyrimidines; Pyrroles; Pyrrolidines; Quinazolines; Sunitinib; Viruses

Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.

Topics: Adenine; Adenosine; Administration, Oral; Animals; Antiviral Agents; Disease Models, Animal; DNA-Directed RNA Polymerases; Ebolavirus; Filoviridae; Filoviridae Infections; Hemorrhagic Fever, Ebola; Humans; Injections, Intramuscular; Macaca fascicularis; Marburg Virus Disease; Marburgvirus; Purine Nucleosides; Pyrrolidines; RNA; Time Factors