Respiratory syncytial virus (RSV), a member of the paramyxovirus family, is the leading cause of infant hospitalization from infectious diseases in the United States. Regular re-infection of adults during seasonal epidemics provides the ground for caregiver-to-baby transmissions, which aggravate the problem. Despite extensive research, no vaccine protection is available and current antibody therapy-based immunoprophylaxis remains reserved for high-risk patients. Recognizing the unmet pediatric clinical need for efficacious, readily applicable and cost-effective RSV therapeutics, it is the overarching goal of this proposal to apply a rigorous drug development approach to the problem and ultimately identify an anti-RSV therapeutic candidate and at least one mechanistically distinct alternative compound that are suitable for IND-enabling formal development. Narrowly focused drug discovery campaigns are at high risk of early stage failure. We hypothesize that a comprehensive anti-RSV approach interrogating the full host-pathogen interactome for pathogen-directed and host-directed drug candidates has the highest prospect of ultimately yielding viable clinical candidates. This is based on the realization that traditional pathogen-directed therapeutics enjoy an excellent clinical record but can be compromised by emerging viral resistance and/or a narrow pathogen indication spectrum, whereas host-directed antivirals promise to overcome these limitations, yet are at present predominantly still in preclinical development. Building on our multiple-year expertise in the development of myxovirus inhibitors, we have in pilot studies engineered a first in class recombinant RSV expressing a luciferase reporter and developed an innovative drug screening protocol that allows the simultaneous identification of pathogen- directed and host-directed antivirals in a single-well setting. Proof-o-concept implementation of this screen has yielded, amongst others, a novel pathogen-specific small-molecule RSV entry inhibitor with exquisite toxicity profile and an innovative host-directed agonist class of cellular antiviral defense pathways. Lead compounds of both series show nanomolar inhibitory activity against pathogenic RSV variants. To maximize the prospect of success of this program and meet the clinical demand for effective RSV therapy, we will diversify the portfolio of anti-RSV candidates by implementing a full-scale drug screening campaign based on the newly established protocol (aim 1). In parallel, the existing leads and, as discovery advances, novel anti-RSV candidates will be mechanistically characterized and their molecular targets identified (aim 2). Candidates with high developmental potential will be subjected to hit-to-lead synthetic optimization guided by in vitro potency, ADME parameters and small-animal pharmacokinetics profiles (aim 3). The efficacy of lead candidates in alleviating key features of RSV bronchiolitis, airway damage, high lung viral load, mucus expression, and pulmonary obstruction, will be assessed in a newly established clinically relevant mouse model of RSV infection (aim 4).
Respiratory syncytial virus infections are the leading cause of infant hospitalization from infectious diseases in the United States, and result in major human morbidity and mortality globally in particular among infants, the elderly, and the immunocompromised. Lack of effective vaccines and small-molecule RSV therapeutics generate high clinical need for the development of innovative therapeutic countermeasures to control RSV spread and improve disease management. Building on an established antiviral program, this project will combine the preclinical development of newly identified lead RSV inhibitors with the diversification of the inhibitor candidate pool through an independent drug screening campaign to ultimately improve public health through novel, applicable RSV therapeutics.
|Yoon, Jeong-Joong; Toots, Mart; Lee, Sujin et al. (2018) Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses. Antimicrob Agents Chemother 62:|
|Ke, Zunlong; Strauss, Joshua D; Hampton, Cheri M et al. (2018) Promotion of virus assembly and organization by the measles virus matrix protein. Nat Commun 9:1736|
|Cox, Robert M; Toots, Mart; Yoon, Jeong-Joong et al. (2018) Development of an allosteric inhibitor class blocking RNA elongation by the respiratory syncytial virus polymerase complex. J Biol Chem 293:16761-16777|
|Thakkar, Vidhi D; Cox, Robert M; Sawatsky, Bevan et al. (2018) The Unstructured Paramyxovirus Nucleocapsid Protein Tail Domain Modulates Viral Pathogenesis through Regulation of Transcriptase Activity. J Virol 92:|
|Hashiguchi, Takao; Fukuda, Yoshinari; Matsuoka, Rei et al. (2018) Structures of the prefusion form of measles virus fusion protein in complex with inhibitors. Proc Natl Acad Sci U S A 115:2496-2501|
|Fearns, Rachel; Plemper, Richard K (2017) Polymerases of paramyxoviruses and pneumoviruses. Virus Res 234:87-102|
|Ha, Michael N; Delpeut, Sébastien; Noyce, Ryan S et al. (2017) Mutations in the Fusion Protein of Measles Virus That Confer Resistance to the Membrane Fusion Inhibitors Carbobenzoxy-d-Phe-l-Phe-Gly and 4-Nitro-2-Phenylacetyl Amino-Benzamide. J Virol 91:|
|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|
|Cox, Robert M; Plemper, Richard K (2017) Structure and organization of paramyxovirus particles. Curr Opin Virol 24:105-114|
|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|
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