Sirtuin 1 – 7 Structural Biology
Computer-aided drug design
Evrys Bio’s broad-spectrum antivirals are based on the discovery that certain human proteins, called sirtuins, normally defend the human (host) cell from being invaded by many different virus-types. Sirtuins regulate the metabolism of the host cell. When a virus infects the host cell, the virus redirects the metabolic machinery of its host to support production of virus DNA and proteins. By modulating sirtuin activity, Evrys Bio drugs restore metabolism that favors the host cell and enhances host defense-mechanisms while eliminating productive conditions for virus propagation. Since host-mediated metabolism is essential to provide the necessary building blocks for the virus, the virus cannot evolve resistance mutations around Evrys Bio drugs.
Three features differentiate Evrys Bio sirtuin-targeted antivirals from currently marketed direct-acting antivirals that target a virus protein: (1) a high barrier to viral resistance, (2) effective against a variety of different virus-types, and (3) therapeutic utility in multiple areas of significant unmet medical need.
Evrys Bio drugs were initially identified in a screen for drug-like chemicals demonstrating modulatory effects on the enzyme activity of any of the seven human sirtuins 1-7. Sirtuins are evolutionarily conserved enzymes that modify other proteins through de-acylation; Evrys Bio founders demonstrated sirtuins are also evolutionarily conserved viral restriction factors (view publication). Sirtuin modulators are drug-like chemicals that increase or decrease the ability of sirtuins to modify downstream proteins. To optimize sirtuin drugs for antiviral use in the clinic, Evrys Bio leverages our world-class expertise in both sirtuin and virus biology starting with structural information about all seven sirtuins and computer-aided drug-design to model the desired drug selectivity, with the desired sirtuin interaction(s), to be validated through X-ray crystallography. Evrys Bio proprietary and drug-like candidates are first validated as antivirals in virus growth assays in primary cells and then in cross-species animal models against diverse viruses spanning enveloped and non-enveloped DNA and RNA viruses. In the clinic, reduction of viremia in patients will provide a predictive disease-modifying biomarker to facilitate early clinical development. Thus, the Evrys Bio sirtuin-based antiviral-platform benefits from the validation of sirtuin-based drugs in viral assays in culture, in animals, and in the clinic, tracking the desired disease-modifying effect to inhibit virus growth through the entire drug-development process.
Computer-aided drug design
Virus- growth assays
Proof of Concept in man
Evrys Bio products will have the potential to transform the practice of medicine by offering treatment options that target a broad-spectrum of viral infections responsible for an entire infectious disease condition, such as respiratory infections. Current virus-targeted therapies, such as influenza antivirals, are only effective against the targeted virus, i.e. influenza A or influenza B, and exclude other respiratory viral infections presenting with similar symptoms, such as respiratory syncytial virus (RSV), SARS virus, and others. In the case of respiratory infections, in a typical season, influenza only accounts for ~20% of such infections referred to by physicians as influenza-like illness. Evrys Bio is developing a portfolio of first-in-class, broad-spectrum antivirals, that can be safely administered without the problem of virally-acquired resistance. The goal is one therapy to target and cure each infectious disease condition. In addition to a pan-respiratory infections antiviral, Evrys Bio has active programs targeting multiple (opportunistic) infections endangering transplant patients and their graft organs; a liver infections antiviral targeting HBV, HCV and HCMV; and for emerging infectious diseases such as Marburg virus, viral encephalitis, Zika, MERS-CoV, and SARS-CoV.
Seasonal flu annually causes considerable morbidity and mortality; its overall burden to the U.S. economy is estimated to be $83 B per year. As the COVID-19 pandemic continues the cost of life, quality of life, and the economy continues to grow. Evrys Bio has leads with activity against alpha and beta coronaviruses (229E and OC43), respiratory syncytial virus and influenza A and B, including strains resistant to current drugs. The targeted patients include those receiving the least benefit from seasonal flu vaccines and the greatest risk of complications, infants and the elderly. The expanded profile will include other respiratory viruses (e.g. SARS-CoV, MERS-CoV, adenovirus). Superior clearance of virus compared to oseltamivir suggests the Evrys Bio antiviral may prevent person-to-person spread.
Some viruses cause disease primarily in immunocompromised patients, such as transplant patients, who are actively immunosuppressed to protect their grafts. Such viruses are “opportunistic”. In transplant patients, active immunosuppression is required to maintain the graft. With suppressed immune systems, patients have increased occurrence of infections and must be actively monitored because the symptoms of infection are also suppressed. Viruses like BKV have no effective antivirals. To treat, immune suppression is reduced until the infection clears, putting the graft organ at risk of rejection. Evrys Bio leads are active against multiple opportunistic viruses including cytomegalovirus. The expanded profile will include herpes, respiratory, and hepatitis viruses.
Emerging infectious diseases can be defined as pathogens which can be easily or moderately disseminated/transmitted, have a moderate to high mortality rate or impact on public health, cause social disruption, and require enhancements for diagnostic capacity or disease surveillance. Evrys leads have shown effectiveness in cell culture models of infection for many different RNA and DNA viruses, enveloped and unenveloped that have been classified as emerging infectious diseases (e.g. Zika, Marburg, Junin, SARS-CoV). Evrys Bio antiviral will have broad-spectrum affect across multiple virus types (e.g. polyomavirus, flavivirus, filovirus, arenavirus, coronaviruses) as well as encephalitic alphaviruses like Venezuelan equine encephalitis virus (VEEV). A broad-spectrum host-targeted antiviral targeting sirtuins will provide a therapeutic option that can be given to vaccinated or unvaccinated individuals, can be combined with traditional virus-targeted direct-acting antivirals (DAAs), and can provide a high barrier to virus-acquired drug resistance. Such a drug can be rapidly manufactured, can be taken in shelf-stable pill form, will not require cold-chain logistics for distribution, and can be stockpiled to anticipate future known, and yet to be identified pathogens. This approach will allow for “flattening of the curve” and lowering the cost of life and disruptions in the world economy in future pandemics
While chronic hepatitis, or liver inflammation, may have no symptoms, it can progress over time to more serious liver ailments including cirrhosis (scarring of the liver), fibrosis (formation of extra fibrous tissue), or even complete liver failure which is fatal. Cirrhosis greatly increases the risk of liver cancer. Recently, there has been a break-through in antiviral therapies that effect a cure for hepatitis C. Along with hepatitis C, hepatitis B and A are the most common viruses infecting the liver; less common but often deadly, is cytomegalovirus, hepatitis D and E. Evrys Bio has initiated a drug discovery program optimizing its sirtuin-based cytomegalovirus antivirals for liver treatment.
Beyond Infections: Oncology
Beyond infectious disease, efficacious sirtuin modulators with clear mechanism of action have multiple indications in the treatment of chronic diseases such as caner. Multiple sirtuin-based drugs have progressed to phase 2, with over 1,255 patients enrolled in completed trials for cancer, diabetes, sepsis, Huntington’s disease and others. However, Evrys Bio believes that the company’s Next Gen sirtuin-drugs provide multiple pharma partnering opportunities across the oncology area. Evrys Bio Next Gen sirtuin-drugs benefit from state-of-the-art science with respect to sirtuin 1 through 7 biology (as opposed to primarily sirtuin 1 for the earlier 1st generation drugs) and demonstrate validated disease modifying biological activity.