Our Science

RdRp Thumb-1

Unlocking a Highly Conserved Vulnerability in Viral Biology

The discovery of RdRp Thumb-1 as a novel, conserved, and cryptic allosteric site represents a transformative milestone in antiviral science. This target lies at the heart of our efforts to disrupt the “one-virus, one-drug” paradigm that has long constrained the field of infectious disease therapeutics. By targeting this key site within the RNA-dependent RNA polymerase (RdRp), we are pioneering a broad-spectrum antiviral approach that holds promise for treating multiple RNA viruses with a single therapeutic.

The discovery of RdRp Thumb-1 as a novel, conserved, and cryptic allosteric site represents a transformative milestone in antiviral science. This target lies at the heart of our efforts to disrupt the “one-virus, one-drug” paradigm that has long constrained the field of infectious disease therapeutics. By targeting this key site within the RNA-dependent RNA polymerase (RdRp), we are pioneering a broad-spectrum antiviral approach that holds promise for treating multiple RNA viruses with a single therapeutic.

Strategy

Science

The RNA-Dependent RNA Polymerase (RdRp)

Strategy

Science

The RNA-Dependent RNA Polymerase (RdRp)

Strategy

Science

The RNA-Dependent RNA Polymerase (RdRp)

A Central Engine for Viral Replication

RdRp is essential for the replication and transcription of RNA viruses, acting as the engine that drives the synthesis of viral RNA. This enzyme is:

01

Ubiquitous

Present across all RNA viruses, including Coronaviridae, Flaviviridae, and Caliciviridae. Highly Conserved: Key structural elements of RdRp remain unchanged across viral families, making it an attractive universal target.

01

Ubiquitous

Present across all RNA viruses, including Coronaviridae, Flaviviridae, and Caliciviridae. Highly Conserved: Key structural elements of RdRp remain unchanged across viral families, making it an attractive universal target.

01

Ubiquitous

Present across all RNA viruses, including Coronaviridae, Flaviviridae, and Caliciviridae. Highly Conserved: Key structural elements of RdRp remain unchanged across viral families, making it an attractive universal target.

02

Highly Conserved

Key structural elements of RdRp remain unchanged across viral families, making it an attractive universal target.

02

Highly Conserved

Key structural elements of RdRp remain unchanged across viral families, making it an attractive universal target.

02

Highly Conserved

Key structural elements of RdRp remain unchanged across viral families, making it an attractive universal target.

The Problem

Traditional antiviral approaches have focused on either nucleoside analog inhibitors, which mimic natural substrates to disrupt RdRp activity, or protease inhibitors, which block viral protein processing. However, these approaches are virus-specific, prone to resistance, and limited in scope. Targeting RdRp Thumb-1 offers a novel solution that transcends these limitations.

A Cryptic and Allosteric Vulnerability

Thumb-1 is a cryptic, highly conserved allosteric site located within the structural framework of the RdRp enzyme. This site is:

Thumb-1 is a cryptic, highly conserved allosteric site located within the structural framework of the RdRp enzyme. This site is:

Thumb-1 is a cryptic, highly conserved allosteric site located within the structural framework of the RdRp enzyme. This site is:

01

Cryptic

Inaccessible under typical conditions, Thumb-1 becomes exposed only under specific conformational states of the polymerase.

01

Cryptic

Inaccessible under typical conditions, Thumb-1 becomes exposed only under specific conformational states of the polymerase.

01

Cryptic

Inaccessible under typical conditions, Thumb-1 becomes exposed only under specific conformational states of the polymerase.

02

Allosteric

Binding to Thumb-1 disrupts the structural and functional integrity of RdRp, inhibiting its ability to synthesize viral RNA.

02

Allosteric

Binding to Thumb-1 disrupts the structural and functional integrity of RdRp, inhibiting its ability to synthesize viral RNA.

02

Allosteric

Binding to Thumb-1 disrupts the structural and functional integrity of RdRp, inhibiting its ability to synthesize viral RNA.

03

Highly Conserved

The Thumb-1 domain is preserved across diverse RNA virus families, reducing the likelihood of resistance and ensuring broad-spectrum applicability.

03

Highly Conserved

The Thumb-1 domain is preserved across diverse RNA virus families, reducing the likelihood of resistance and ensuring broad-spectrum applicability.

03

Highly Conserved

The Thumb-1 domain is preserved across diverse RNA virus families, reducing the likelihood of resistance and ensuring broad-spectrum applicability.

Strategy

Science

Thumb-1

Strategy

Science

Thumb-1

Strategy

Science

Thumb-1

Strategy

Science

A Revolutionary New Approach

Strategy

Science

A Revolutionary New Approach

Strategy

Science

A Revolutionary New Approach

Broad-Spectrum Potential

Unlike nucleoside analogs or protease inhibitors, which are virus-specific, targeting Thumb-1 disrupts the replication machinery common to all RNA viruses. This approach breaks away from the “one-virus, one-drug” paradigm, offering a universal solution for RNA virus infections.

High Barrier to Resistance

High Barrier to Resistance

The conserved nature of Thumb-1 significantly lowers the likelihood of resistance mutations, a critical limitation of existing antiviral therapies. The essential role of Thumb-1 in polymerase function ensures that structural alterations to evade drug binding would compromise viral fitness.

Allosteric Inhibition

Allosteric Inhibition

Allosteric targets like Thumb-1 provide a unique mechanism of action that complements existing antiviral strategies. By binding to a site distinct from the active site, Thumb-1 inhibitors avoid direct competition with natural substrates, enhancing both specificity and efficacy.

Overcoming Therapeutic Limitations

Overcoming Therapeutic Limitations

Targeting Thumb-1

Our research uncovered the Thumb-1 site through advanced structural biology techniques, including cryo-electron microscopy and computational modeling. Key insights include:

01

Structural Access

Thumb-1 is revealed only during specific enzymatic conformational changes, providing an opportunity for targeted inhibition.

01

Structural Access

Thumb-1 is revealed only during specific enzymatic conformational changes, providing an opportunity for targeted inhibition.

01

Structural Access

Thumb-1 is revealed only during specific enzymatic conformational changes, providing an opportunity for targeted inhibition.

02

Functional Disruption

Binding to Thumb-1 causes destabilization of the RdRp complex, halting RNA synthesis and effectively silencing viral replication.

02

Functional Disruption

Binding to Thumb-1 causes destabilization of the RdRp complex, halting RNA synthesis and effectively silencing viral replication.

02

Functional Disruption

Binding to Thumb-1 causes destabilization of the RdRp complex, halting RNA synthesis and effectively silencing viral replication.

03

Conservation Across Viruses

Comparative studies confirmed the presence of Thumb-1 across major RNA virus families, validating its potential as a universal antiviral target.

03

Conservation Across Viruses

Comparative studies confirmed the presence of Thumb-1 across major RNA virus families, validating its potential as a universal antiviral target.

03

Conservation Across Viruses

Comparative studies confirmed the presence of Thumb-1 across major RNA virus families, validating its potential as a universal antiviral target.

Strategy

Science

Targeting Thumb-1

Strategy

Science

Targeting Thumb-1

Strategy

Science

Targeting Thumb-1

Strategy

Science

A New Paradigm

Strategy

Science

A New Paradigm

Strategy

Science

A New Paradigm

Disrupting the One-Virus, One-Drug Model

Traditional antiviral therapies have been reactive, addressing individual viral threats with tailored drugs. This approach is both resource-intensive and insufficient for pandemics involving novel or multiple viral strains. RdRp Thumb-1 inhibitors represent a shift toward proactive, universal therapeutics:

01

Single Therapy for Multiple Viruses

Treats a broad range of RNA viruses, from coronaviruses to flaviviruses, with one drug.

01

Single Therapy for Multiple Viruses

Treats a broad range of RNA viruses, from coronaviruses to flaviviruses, with one drug.

01

Single Therapy for Multiple Viruses

Treats a broad range of RNA viruses, from coronaviruses to flaviviruses, with one drug.

02

Pandemic Preparedness

Addresses both current viral threats and potential future outbreaks.

02

Pandemic Preparedness

Addresses both current viral threats and potential future outbreaks.

02

Pandemic Preparedness

Addresses both current viral threats and potential future outbreaks.

03

Resource Optimization

Streamlines development pipelines and accelerates time-to-market.

03

Resource Optimization

Streamlines development pipelines and accelerates time-to-market.

03

Resource Optimization

Streamlines development pipelines and accelerates time-to-market.

Global Health Impact

  • Broad-spectrum antivirals based on Thumb-1 inhibitors have the potential to protect billions of people worldwide.

  • They provide a scalable solution for resource-limited settings and enhance global pandemic preparedness.

Scientific Advancement

  • Redefines antiviral drug discovery by focusing on structural vulnerabilities shared across viral families.

  • Opens new avenues for the development of second-generation inhibitors and combination therapies.

Strategy

Science

Implications of RdRp Thumb-1 Discovery

Strategy

Science

Implications of RdRp Thumb-1 Discovery

Strategy

Science

Implications of RdRp Thumb-1 Discovery

Revolutionizing Antiviral Treatment

learn more

Partnerships

Join Us in Advancing Antiviral Innovation

Our pipeline is built on the foundation of bold science and transformative potential. We welcome partnerships to accelerate the development and deployment of these life-saving therapies.

Pipeline

Broad-Spectrum Solutions for Global Health

Our portfolio includes therapies for Hepatitis C, SARS-CoV-2, Influenza, and Norovirus. Discover how we’re targeting unmet needs across multiple therapeutic areas.