SBIR-STTR Award

Smallpox virus (variola) is a potential biological weapons agent due to its ease of dissemination, person to- person transmissibility and potential to cause widespread illness and death. Smallpox virus is classified as a Category A bioweapons agent by the Centers for Disease Control and Prevention (CDC). Currently, there are no FDA-approved antiviral drugs to prevent or treat smallpox infection. The overall goal of our Smallpox Virus Biodefense Program is to discover and develop small molecule drugs for prevention and treatment of smallpox virus infection. The specific aims of this Phase 1 application are to: 1. Establish a validated virus-specific high throughput-screening assay using a cowpox virus (BSL-2) surrogate for authentic variola virus. 2. Identify specific inhibitors that target wild type and drug resistant variants of cowpox virus from VIROPHARMA's proprietary chemically diverse library of over 400,000 small molecule compounds. 3. Characterize inhibitor compounds ("hits") for chemical tractability, antiviral potency and spectrum and selectivity in order to identify promising "quality hits". 4. Confirm antiviral specificity and selectivity of quality hits against the authentic variola virus in cell culture (performed through collaborating laboratories); 5. Investigate the mechanism of antiviral action of "confirmed quality hits"; and 6. Conduct initial drug metabolism, genotoxicity & pharmacokinetic evaluations on confirmed quality hits. The end result of Phase 1 work will be identification of quality hits specific for variola virus. Advancement of these compounds in Phase 2 will involve: (1) hit-to-lead medicinal chemistry to identify leads with good potential for chemical structure-biological activity relationships (SAR); (2) lead compound optimization for antiviral potency, selectivity and spectrum of antiviral activity and drug metabolic and pharmacokinetics properties; (3) mechanism of action and drug resistance characterizations; and (4) efficacy evaluations in suitable animal models. At the end of Phase 2, we anticipate to have identified at least one pre-clinical candidate compound that is suitable for advancement into formal IND toxicological and model animal efficacy evaluations for the prevention and treatment of smallpox virus infection.

Thesaurus Terms:
Poxviridae, antiviral agent, drug design /synthesis /production, drug screening /evaluation, high throughput technology, smallpox virus, virus replication drug resistance bioterrorism /chemical warfare, laboratory rat, tissue /cell culture

Recent concerns over the use of smallpox (variola) virus as a biological weapon have prompted renewed interest in development of small molecule therapeutics that target variola virus replication. Variola virus is highly transmissible and causes severe disease in humans resulting in high mortality rates. Currently, there is no FDA-approved drug for the prevention or treatment of smallpox. The overall goal of our smallpox antiviral program is to advance through FDA approval at least one small molecule antiviral drug for treatment and prevention of smallpox that will be safe, effective and orally administered as a capsule, tablet or liquid for treatment, post-exposure prophylactic and prophylactic applications. The objective of this SBIR Phase II smallpox virus project is to advance the early stage variola virus-specific antiviral compounds discovered during our SBIR Phase I work into chemical optimization, through animal efficacy and IND-enabling toxicology, to clinical development stage candidates for which we will submit IND applications. Human safety and pharmacokinetic studies are beyond the scope of the Phase II work plan. At the end of this 3-year SBIR Phase II Smallpox program, we anticipate that we will submit at least one IND application for an antiviral drug candidate for the treatment and prevention of smallpox and identify at least one additional smallpox preclinical candidate. The availability of smallpox virus-specific antiviral drugs will address national and global security needs by acting as significant deterrents and defenses against use of smallpox virus in potential bioterrorist attacks. Antiviral drugs may be readily stockpiled and rapidly deployed in the event of a smallpox virus outbreak. Since antiviral drugs are easily administered (oral pill or liquid) and exert their antiviral effect rapidly (within hours of administration), they will serve to effectively treat diseased patients, protect those suspected of being exposed to the pathogen (post-exposure prophylaxis), and assist in the timely containment of the outbreak.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
Antiviral Agent, Chemical Structure Function, Communicable Disease Control, Drug Design /Synthesis /Production, Inhibitor /Antagonist, Nonhuman Therapy Evaluation, Pharmacokinetics, Smallpox Virus, Virus Replication Drug Administration Rate /Duration, Drug Adverse Effect, Drug Resistance, Microorganism Disease Chemotherapy, Oral Administration Primate, Biotechnology, Bioterrorism /Chemical Warfare, Laboratory Mouse, Laboratory Rat