Antiviral Programs
26 families of viruses are known to cause disease in humans.
The diversity between viral families is staggering¬. Different viruses may utilize different genetic material, infect and propagate within different organ tissues, and present themselves in hosts with different types of symptoms ranging from mild to fatal. For example, Herpes Simplex Virus (herpes) has a genome made of DNA whereas Human Immunodeficiency Virus (HIV) and Influenza Virus (flu) use RNA. Flu infects the lungs, while HIV infects cells of the immune system. Many people infected with herpes never develop symptoms, while HIV is responsible for hundreds of thousands of deaths each year.
One thing all viruses have in common is assembly.
All viruses have a protein shell—their capsid—made from several copies of viral proteins which have been assembled into a distinct structure. Historically, the prevailing view of viral capsid assembly has been that the process happens spontaneously, requiring no input of energy or participation from the host’s proteins. However, when Prosetta’s founders tracked viral proteins within Cell Free Protein Synthesis and Assembly (CFPSA) systems at their academic labs, they discovered that viral capsid assembly is an energy-dependent process facilitated by the host’s enzymes (see Lingappa, 1997).
Prosetta’s founders hypothesized that host-catalyzed viral assembly could be a “drug-able” pathway. We therefore adapted the CFPSA system into a moderate-throughput screen and began searching for compounds that block the assembly of a completed viral capsid from its constituent monomers. Compounds from a library of 150,000 drug-like small molecules were screened against capsid assembly for essentially all families of viruses responsible for causing human disease. Prosetta’s work on antivirals is now focused on advancing hits from the CFPSA screen in three distinct program areas— The Pan-respiratory Program, the HIV Program, and the Neglected Viral Disease Program.
Diagram of CFPSA screen for small molecule viral assembly modulators. Lingappa, et. al. Host-rabies virus protein-protein interactions as druggable antiviral targets. PNAS, 2013.
In the Pan-Respiratory Program, Prosetta has developed one compound with activity against all families which cause human respiratory disease.
An early compound from the series, PAV-431 is active in cell culture at 100nM or lower against viruses in Adenoviridae, Herpesviridae, Paramyxoviridae, Coronaviridae, Orthomyxoviridae, and Picornaviridae families. The compound has shown activity against SARS-CoV-2 in human bronchial epithelial cells from lung donors cultured to an air-liquid interface, a “gold standard” model for translatability to human efficacy. The compound’s antiviral activity has been validated against respiratory syncytial virus (RSV) and porcine epidemic diarrhea virus (PEDV) in animals. An advanced compound from the series, PAV-104 displays nanomolar efficacy against multiple strains of SARS-CoV-2 while maintaining safety in mice at a doses above 50 mg/kg.
Activity of Prosetta Pan-Respiratory Antiviral Compound PAV-431. Muller-Schiffmann et. al. A Pan-respiratory Antiviral Chemotype Targeting a Transient Host Multiprotein Complex. Biorxiv, 2022.
Compounds in the series appear to target 14-3-3, a protein known to carry out allosteric modulation in a number of cellular pathways. Chemical photocrosslinking experiments under native and denatured conditions have shown that, while the compounds directly target 14-3-3, they indirectly target other proteins (including VCP, CAPN2, and P21/SQSTM1) through transient co-associations. Drug Resin Affinity Chromatography experiments have shown that only a small percentage of cellular 14-3-3 is targeted by the compounds. As the chemical series has progressed (both in activity and safety) advanced compounds, such as PAV-104, have become selective for the subset of 14-3-3 involved in disease-specific states.
The development of a pan-respiratory antiviral drug would be a novel solution to both major infections, like the coronavirus pandemic, and minor problems like the common cold. See our preprint manuscript “A Pan-Respiratory Antiviral Chemotype Targeting a Transient Host Multiprotein Complex” on Biorxiv for more information.
In the HIV Program, Prosetta has discovered three separate classes of drugs with unprecedented activity against HIV. The first class of drugs appears to direct the HIV gag protein to a non-ubiquitin-mediated proteasomal pathway of degradation, suggesting a novel means of augmenting MHC class I presentation to repair the T cell deficit typically associated with long-term HIV. The second class of drugs results in release of non-infectious viral particles due to aberrant capsid formation, with no effect on the proteolytic maturation of HIV proteins that accompanies normal capsid assembly (cleavage of p55 to p24). The third class of drugs displays anti-HIV activity after the virus has entered the cell but before there is any expression of viral genes, representing a novel means of preventing the re-infection of already cleared compartments. With further advancement, it is possible that these three drugs— alone or in combination— will make an essential contribution to a long-awaited cure for HIV. See our academic collaborator’s paper “Identification of an Antiretroviral Small Molecule That Appears To Be A Host Targeting Inhibitor of HIV-1 Assembly” in the Journal of Virology for more information.
In the Neglected Viral Disease program, the Prosetta platform has been applied to severe viruses which have received comparatively less attention because they predominantly affect communities in developing countries. Prosetta has identified small molecules active against rabies, dengue, pox, nipah, ebola, and other viruses. The Prosetta approach towards neglected viral disease has the potential to vastly reduce the global burden of disease and the suffering which accompanies it. See our paper “Host-Rabies Virus Protein-Protein Interactions as Druggable Antiviral Targets” in PNAS for more information.
Prosetta is actively seeking academic and industry partnerships to advance our antiviral programs. If you are interested in collaborating or investing resources, please contact us at info@prosetta.com