We currently do not have effective vaccines or antiviral drugs for most of the viral diseases that afflict humans. Antiviral therapies that enable long-term control over human immunodeficiency virus (HIV) infection and cure chronic hepatitis C virus (HCV) have been landmark successes in the treatment of viral infections. These therapies work using multiple direct-acting antivirals (DAAs) that halt viral replication by potently inhibiting or deranging the function of viral proteins, generally enzymes such as viral polymerases and proteases. Development of our current arsenal of DAAs has required significant investments that cannot be easily duplicated to combat the hundreds of other existing and emerging viral pathogens on an individual basis. Prioritization of viral pathogens for drug development efforts is challenging and unpredictable, currently requiring a balance of efforts to develop therapies for widespread viral diseases that affect hundreds of millions annually, such as chronic hepatitis B and human influenza viruses, with efforts to develop countermeasures against less predictable emerging and re-emerging viruses, such as Zika virus and SARS CoV-2, for which delaying until the virus is a major threat makes it difficult to have an impact on the immediate crisis.
Compounding these challenges is the emergence of drug resistance, which, as shown for HIV and HCV, can occur rapidly during monotherapy with only a single DAA. Many of the most threatening viruses (e.g., influenza, dengue, Chikungunya, Zika, respiratory syncytial viruses) have RNA genomes that mutate rapidly due to limited or no proofreading function in the viral polymerase. For viruses like these that cause annual epidemics and are transmitted constantly, resistance to a single drug that inhibits a viral enzyme is expected to rise rapidly and may already exist in nature, as was observed for the influenza virus neuraminidase inhibitor oseltamivir and endonuclease inhibitor xoflusa. Another inherent limitation of monotherapy against a single target is the high systemic exposure required to ensure sufficient inhibitory potency in vivo and the emergence of drug resistance. While combination therapy with multiple DAAs that act via independent targets and mechanisms is a proven way to achieve the necessary level of antiviral potency and avoid resistance, our development of these combinations is resource limited. Due to these challenges, antiviral strategies that use alternative targets, mechanisms, and modalities to combat viral diseases are of considerable interest in developing new classes of antivirals with increased spectrum of activity and higher barrier to resistance.
Targeted protein degradation (TPD) has emerged as a pharmacological strategy in which a small molecule is used to target a protein of interest to a cellular degradation pathway. This has most commonly been accomplished by using bifunctional chimeric molecules to recruit a specific E3 ubiquitin ligase to the target protein of interest, leading to its ubiquitination and degradation by the proteasome. While TPD-based drugs have advanced rapidly with >20 currently in clinical for cancer and inflammation, application of TPD in the area of infectious diseases has only recently begun to emerge.
Our lab has been at the forefront of developing targeted protein degradation (TPD) as an antiviral strategy. Our approach has been to synthesize bifunctional molecules (known as “degronimids,” “PROTACs,” or “degraders”) that have a ligand for the target of interest covalently linked to a ligand for a specific E3 ubiquitin ligase. Rather than inhibiting or deranging the function of the viral target protein, the degrader molecule induces formation of a ternary complex with an E3 ligase, leading to ubiquitination and proteasomal degradation of the target protein. Unlike small molecule inhibitors, which have occupancy-driven pharmacology and thus must bind with high affinity to exert significant antiviral activity, degraders exhibit event-driven pharmacology and only require affinity and residence time sufficient to allow formation of the ternary complex. Due to this tolerance of lower affinity binding, we have hypothesized that antiviral degraders may be better able than classical inhibitors to inhibit genetically diverse viral species and to suppress potentially resistant mutants that arise during drug treatment. As proof of concept, we used telaprevir, an FDA-approved inhibitor of the hepatitis C virus (HCV) NS3-4A protease, to develop degraders of HCV NS3 and to show that NS3 degrader DGY-08-097 inhibits telaprevir-resistant mutants.
We have since extended our efforts to develop TPD-based antivirals against a variety of other viral proteins, with a keen interest in viral proteins that are considered “undruggable” due to their lack of a classical active site.
Dr. Yang has pioneered the development of antivirals that act via novel targets and mechanisms beyond traditional direct-acting antivirals (DAAs), as well as DAAs with unprecedented mechanisms and/or activity. For example, she made a seminal discovery that an allosteric inhibitor of human Abl kinase inhibits replication of the dengue virus by both Abl-dependent and Abl-independent mechanisms. These insights launched community-wide interest in repurposing non-antiviral drugs as antiviral agents, most recently seen in numerous such efforts to target SARS-CoV-2.
Furthermore, Dr. Yang’s research on targeting the flavivirus envelope protein, E, has resulted in inhibitors with broad activity across the flavivirus genus, thus creating important tools for this important family of human pathogens. As an illustration, she made an intriguing discovery that complete blocking of fusion occurs when only a subset (~1/5) of the 180 functionally redundant copies of E on the virion surface are inhibitor-bound.
Additionally, Dr. Yang has led the way in developing antiviral inhibitors with unique mechanisms of action, such as covalent inhibitors that target host protein(s) to thwart viral replication, and degrade molecules that result in viral protein degradation, rather than inhibition, and exhibit broader activity and higher barriers to resistance.
In parallel, Dr. Yang has made major inroads into understanding how viruses affect membrane properties of the host cell, a major unexplored area in virology. This work has revealed previously unappreciated virus-specific lipid selectivity, and established tools for studying how host cell lipid structure and function affect viral RNA replication.
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