Smallpox (caused by variola virus infection) was one of the most destructive diseases in human history, resulting in 300-500 million deaths in the twentieth century alone until it was finally eradicated in 1980. Following elimination of variola virus, global vaccination programs were eventually halted and as a result, most of the world's population is no longer immunologically protected from smallpox nor does it enjoy cross- protection to other orthopoxviruses. There are two drugs approved for smallpox disease, however, both compounds possess significant limitations. A lack of therapeutic options for treating orthopoxvirus infections continues to expose the population to grave risk from a smallpox bioweapon as well as future zoonotic orthopoxvirus infections. During the course of the Phase I funding period, we will execute a hit finding campaign against a library of >200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjected to follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interesting of these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activity relationships (SAR). The overall goal of this project is to discover one or more novel lead series which is defined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against variola virus and other orthopoxviruses with minimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that will advance the program from Early Lead Optimization through to Candidate Selection.
Public Health Relevance Statement: PROJECT NARRATIVE In addition to safe and effective vaccines, direct-acting antivirals with complementary mechanisms of action, patterns of resistance and improved toxicity profiles are desperately needed for the Strategic National Stockpile (SNS) to adequately deter the use of smallpox as a bioweapon and to prepare for zoonotic orthopoxviruses with pandemic potential. Following the eradication of smallpox and the subsequent end of the global vaccine campaign, most of the world's population lost immunological protection to variola virus and to infection by all other orthopoxviruses. As a result, there has been a significant increase in the number of orthopoxvirus spill over events from animal reservoirs into humans. To better prepare for both natural and deliberate threats from orthopoxviruses, we propose high throughput screening of a diversified 200,000 small- molecule library to identify novel antiviral inhibitor classes for the treatment of smallpox disease and other orthopoxviruses with pandemic potential.
Project Terms: 21+ years old; Adult Human; adulthood; Adult; Africa; Animals; domesticated animal; Domestic Animals; Wild Animals; inhibitor; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral compound; anti-viral drugs; anti-viral medication; anti-viral therapeutic; anti-virals; antiviral compound; antiviral medication; antiviral therapeutic; Asia; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Cowpox virus; Cow Pox Virus; Cessation of life; Death; Disease; Disorder; Disease Outbreaks; Outbreaks; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Exhibits; Future; Goals; Recording of previous events; History; histories; Human; Modern Man; indexing; Infant; Infection; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Middle East; Military Personnel; Armed Forces Personnel; Military; military population; Monkeypox virus; Monkey Pox Virus; Monkeypoxvirus; mpxv; Drug Kinetics; Pharmacokinetics; Probability; Public Health; Risk; Smallpox; Variola; small pox; variola major; South America; Structure-Activity Relationship; chemical structure function; structure function relationship; Testing; USSR; Soviet Union; Union of Soviet Socialist Republics; Vaccination; Vaccines; Vaccinia; Vaccinia virus; Poxvirus officinale; recombinant vaccinia virus; Virus Diseases; Viral Diseases; viral infection; virus infection; virus-induced disease; Virus Inhibitors; viral inhibitor; Virus; Zoonoses; Zoonotic; Zoonotic Infection; conference; convention; summit; symposia; symposium; Family member; cross protection; cross immunity; improved; Surface; Phase; Variation; Variant; Series; Vaccination Programs; Immunization Programs; Orthopox virus; Orthopoxvirus; Susceptibility; Predisposition; Individual; Viral Activity; Viral Function; Viral Physiology; Funding; Case Fatality Rates; HPMPC; Cidofovir; Therapeutic; Genetic; Exposure to; programs; Event; Oral; Pattern; Viral; cytotoxicity; Lytotoxicity; success; small molecule libraries; chemical library; Toxic effect; Toxicities; novel; Geographic Distribution; Prevention; Reporting; Variola major virus; P variolae; P. variolae; P.variolae; Poxvirus variolae; Smallpox virus; Variola virus; small pox virus; Property; response; Bioterrorism; Biological Terrorism; high throughput screening; High Throughput Assay; monolayer; small molecule; Incubated; Dose; Molecular Target; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; transmission process; Transmission; Preparation; preparations; Development; developmental; novel virus; pathogen; Population; resistant; Resistance; human disease; aerosolized; candidate selection; lead series; lead optimization; biological weapon; bioweapon; pandemic potential; pandemic concern; pandemic risk; pandemic threat; drug-like compound; drug-like chemical; drug-like molecule
