When it comes to antiviral treatments, traditional approaches have predominantly adopted a 'one virus, one drug’ dogma. This method struggles to keep pace with the rapid emergence and evolution of viral pathogens, highlighting a critical need for more broad solutions. The infectious disease program at Model Medicines has addressed this challenge by pioneering an antiviral strategy: one drug for many viruses.

In a recent C&EN article, Bethany Halford (with support from Max Barnhart, Rowan Walrath, and Benjamin Plackett) highlights how numerous pharmaceutical companies continue expanding their COVID-19 antiviral pipelines, specifically targeting the SARS-CoV-2 main protease (Mpro). Companies such as Pfizer, Shionogi, Enanta Pharmaceuticals, Aligos Therapeutics, and Insilico Medicine are developing antivirals focused primarily on this key protein. 

A new biotech launched in 2024, Red Queen Therapeutics, and backed by Apple Tree Partners with funding from BARDA, employs stapled lipopeptides to target viral fusion proteins, specifically the HR1 domain, aiming for pan-influenza efficacy. Despite this innovative approach, it remains largely virus-specific, which may limit its broad applicability and leave it vulnerable to resistance (BioCentury).

Challenges with Mpro and HR1 Antiviral Targets

Historically, Covid antivirals have targeted specific viral proteins like the main protease (Mpro) and more recently the Heptad Repeat 1 (HR1) domains. While these targets have been effective against particular viruses, they face considerable challenges, especially viral mutation and resistance.

Mpro Inhibitors

The main protease (Mpro) of SARS-CoV-2 is a common antiviral target. Examples include Pfizer’s ibuzatrelvir and Shionogi’s ensitrelvir. Despite their effectiveness, these antivirals often encounter issues such as viral resistance and side effects. While newer versions like Pfizer’s ibuzatrelvir have improved some issues, they remain narrowly specific to one virus, limiting their broader use and resilience against mutations (Pfizer article, C&EN).

HR1 Inhibitors

Inhibitors targeting the Heptad Repeat 1 (HR1) domain, such as those developed by Red Queen Therapeutics, have been effective in treating HIV and other viruses. However, their effectiveness remains limited due to their specificity for individual viruses, making them vulnerable to resistance.

A Paradigm Shift: Targeting the RdRp Thumb-1 Domain

In contrast, the infectious disease program at Model Medicines pioneered a novel and potentially transformative antiviral strategy by targeting the RNA-dependent RNA polymerase (RdRp) Thumb-1 site. Unlike traditional viral drug targets, RdRp Thumb-1 is a cryptic, allosteric pocket highly conserved across multiple RNA viruses. This conservation suggests a reduced likelihood of resistance mutations developing, as mutations within such structurally constrained regions would significantly impair viral function, presenting substantial difficulties for resistance evolution (RdRp Thumb-1 Discovery). 

Leveraging the Model Medicines’ AI-driven GALILEO™ platform, we identified MDL-001 as a broad-spectrum antiviral exhibiting potent efficacy against multiple viruses across multiple viral families, including SARS-CoV-2 and its variants, Hepatitis C, Norovirus, and Influenza. Critically, MDL-001 demonstrated substantial antiviral efficacy in vivo, notably reducing SARS-CoV-2 viral accumulation in mouse lungs by 2.9 Log10, significantly exceeding the efficacy observed for Paxlovid (1.4–1.9 Log10) when tested under comparable conditions at the Icahn School of Medicine at Mount Sinai by Adolfo García-Sastre and Kris White (Adolfo and Kris as well as their team are co-authors on Model Medicines’ recent preclinical preprint MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases). This performance positions MDL-001 alongside or above FDA-approved antivirals such as remdesivir and Paxlovid.

While Pfizer's ensitrelvir has recently shown promise as a prophylactic antiviral as pointed out by Alice Park at TIME, MDL-001 offers complementary advantages, notably its broad-spectrum antiviral efficacy, established safety profile, and excellent tolerability, enabling prophylactic, pre-exposure administration.

Building NCEs Libraries with GALILEO™

Expanding on this achievement, we leveraged GALILEO™ to explore vast chemical space exceeding 53 trillion compounds, successfully identifying a library of 12 novel, next-generation antiviral candidates with enhanced specificity and potency against viral targets. GALILEO’s generative and multimodal discovery tools to create trillions of new chemical entities (NCEs) from MDL-001’s pharmacophoric scaffold and select a library of highly specific and optimized compounds for next-generation broad-spectrum antiviral development. Each candidate demonstrated antiviral activity in vitro, marking a remarkable 100% hit rate and showcasing significant chemical novelty compared to existing antivirals (GALILEO Generative AI).

Model Medicines' discovery and validation of the RdRp Thumb-1 site as a broad-spectrum antiviral target represents a crucial paradigm shift, fundamentally enhancing antiviral drug development strategies.​

The clinical potential for MDL-001 extends beyond conventional treatment, introducing a new antiviral paradigm akin to antibiotic management in bacterial infections. Upon patient presentation, MDL-001 could be administered as a broad-spectrum antiviral therapy to rapidly manage infection. This approach mirrors successful antibiotic strategies, offering immediate broad coverage followed by precise pathogen-targeted therapy, significantly advancing humanity’s response capabilities against viral pandemics. 

By transcending the traditional limitations associated with the one-drug-for-one-virus paradigm, RdRp Thumb-1 inhibitors offer powerful solutions to improve global preparedness for current and emerging viral threats. 

To learn more about Model Medicines’ pipeline, visit https://modelmedicines.com/pipeline