It is the overarching goal of this project to spearhead novel therapeutic strategies that are designed to transform the traditional one-drug, one-bug approach of antiviral therapy to a one-drug class, multiple-bugs paradigm. This is driven by the realization that high cost and lack of flexibility of current pharmaceutical manufacturing technologies, continuous viral evolution and the emergence of novel viral pathogens demand heightened flexibility of the drug discovery and development process. Pathogens of the myxovirus families have been chosen for this program because myxoviruses such as influenza virus, parainfluenza viruses, respiratory syncytial virus and measles virus are a major threat to human health, and many fundamentals of pathogen biology are conserved between different myxovirus family members. To meet future clinical challenges of antiviral therapy, this project will build on the solid foundation provided by our established anti- myxovirus program and pursue the development of innovative small-molecule antivirals with broadened anti- myxovirus target spectrum in two complementary, but independent avenues. A novel class of measles virus RNA-dependent RNA-polymerase (RdRp) inhibitors will be transformed into a flexible anti-paramyxovirus platform through pharmacophore extraction and structure-based scaffold engineering or design. In parallel, a host directed anti-myxovirus approach will be pursued that blocks host pathways required for virus replication. The first approach originates from a therapeutic candidate blocker of the measles virus polymerase (L) protein that was developed by our team. Driven by the hypothesis that the spatial organization of the inhibitor target site is largely conserved among related paramyxovirus L proteins, photoreactive analogs will be employed as innovative molecular probes to optimize a folding-competent L fragment identified in pilot studies for co- crystallization. Extraction of a molecular pharmacophore will enable the transformation of this virus-specific scaffold to a versatile anti-paramyxovirus platform through i silico design against related L targets in conjunction with chemical synthesis and biotesting (aim 1). The parallel approach rests on the hypothesis that host-directed antivirals show a broadened pathogen target spectrum due to dependence of related viral families on a similar set of host factors. Our program has identified a nanomolar influenza and paramyxovirus blocker class with host-directed profile, low toxicity and good pharmacokinetics. This scaffold will be fully mechanistically characterized and its host target determined. In addition, a novel, innovative high-throughput screening protocol and data-mining of system-wide host-influenza interaction screens will be implemented to identify independent host targets and diversify the host-directed hit portfolio (aim 2). Commencing immediately with the leads already identified in pilot studies and supplemented with newly discovered promising hits as the project progresses, drug-like properties of lead candidates will be synthetically advanced, select ADME properties determined and pharmacokinetics, small-animal efficacy, and biotoxicity determined (aim 3).
Myxoviruses comprise groups of viral pathogens that cause major human diseases, including influenza and flu- like illness, measles and mumps, and several important animal diseases. Emerging resistance against licensed influenza drugs, the threat of a pandemic of highly pathogenic influenza strains, lack of vaccines against parainfluenza viruses and respiratory syncytial virus, and re-emergence of mumps and measles virus mandate the development of innovative therapeutics. This project will improve public health by exploring innovative anti-myxovirus strategies and developing therapeutic lead classes with broadened myxovirus target spectrum.
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|Cox, Robert M; Krumm, Stefanie A; Thakkar, Vidhi D et al. (2017) The structurally disordered paramyxovirus nucleocapsid protein tail domain is a regulator of the mRNA transcription gradient. Sci Adv 3:e1602350|
|Jiménez-Somarribas, Alberto; Mao, Shuli; Yoon, Jeong-Joong et al. (2017) Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex. J Med Chem 60:2305-2325|
|Fearns, Rachel; Plemper, Richard K (2017) Polymerases of paramyxoviruses and pneumoviruses. Virus Res 234:87-102|
|Cox, Robert; Plemper, Richard K (2016) Structure-guided design of small-molecule therapeutics against RSV disease. Expert Opin Drug Discov :1-14|
|Hotard, Anne L; Lee, Sujin; Currier, Michael G et al. (2015) Identification of residues in the human respiratory syncytial virus fusion protein that modulate fusion activity and pathogenesis. J Virol 89:512-22|
|Ader-Ebert, Nadine; Khosravi, Mojtaba; Herren, Michael et al. (2015) Sequential conformational changes in the morbillivirus attachment protein initiate the membrane fusion process. PLoS Pathog 11:e1004880|
|Chung, Hokyung K; Jacobs, Conor L; Huo, Yunwen et al. (2015) Tunable and reversible drug control of protein production via a self-excising degron. Nat Chem Biol 11:713-20|
|Yan, Dan; Weisshaar, Marco; Lamb, Kristen et al. (2015) Replication-Competent Influenza Virus and Respiratory Syncytial Virus Luciferase Reporter Strains Engineered for Co-Infections Identify Antiviral Compounds in Combination Screens. Biochemistry 54:5589-604|
|Cox, Robert; Plemper, Richard K (2015) The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics. Front Microbiol 6:459|
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