The HBV core-protein forms the viral nucleocapsid and is an attractive target for the treatment of viral infection. Capsid inhibitors (CIs) bind at the core-protein dimer of dimer interface, and this leads to aberrant assembly of the nucleocapsid thereby blocking the production of a new virus. Additionally, certain CIs exploit the same dimer-dimer binding site on the mature rcDNA-filled capsid to destabilize it and block the establishment of infection.

HBV surface antigen (HBsAg) is believed to play a major role in maintaining persistent infection in chronic hepatitis B patients. HBV RNA destabilizers inhibit enzymatic activities of noncanonical poly(A) polymerases PAPD5 and PAPD7, destabilize HBV RNA, and suppress viral protein productions, including HBsAg.  AB-161 is our next-generation liver-centric HBV RNA destabilizer targeting PAPD5/7 to reduce HBV RNA and HBsAg in multiple HBV cell-based models and in AAV-HBV infected mice.

Conventional direct-acting antivirals have occupancy-driven pharmacology and require high affinity-binding for antiviral efficacy. Small molecules that instead induce degradation of their target (antiviral degraders) can potentially exert significant antiviral activities without high affinity and residence times due to their event-driven pharmacology. I will describe my group’s proof-of-concept work developing antiviral degraders and comparing the ability of these compounds to address viral genetic diversity when compared to functional inhibitors.

Respiratory syncytial virus (RSV) infection causes substantial morbidity and mortality, yet therapeutics are limited. EDP-323 is a novel small molecule, non-nucleoside RSV L-protein inhibitor developed as potential treatment for RSV infection. EDP-323 has sub-nanomolar potency against RSV-A and RSV-B lab strains and clinical isolates in multiple cell culture models of infection. Mechanism of action studies showed inhibition of RSV transcription and replication. EDP-323 protected BALB/c mice from viral-induced changes in body and lung weights, lung histopathology, inflammatory cytokine production, and significantly reduced viral replication. Together, these data support further evaluation of EDP-323 as a potential RSV treatment.

There is a need for safe, effective, and simple-to-use oral SARS-CoV-2 antivirals for use by people who take common medications for comorbid conditions. PBI-0451 has demonstrated potent pan-coronaviral antiviral activity in vitro, favorable nonclinical and clinical safety and tolerability to date, and a clinical PK profile anticipated to provide potent antiviral activity against SARS-CoV-2. PBI-0451 as a stand-alone agent is currently in Phase 2 studies in patients with COVID-19.

Direct Acting Antivirals (DAA) have been widely acknowledged as the backbone in combating virus infections, e.g. HIV and HCV, ascribing to their fast onset effect and in general low on-target safety concern. In this talk, we will present two stories on the discovery and developments of novel RSV fusion inhibitor (currently Ph3) and HBV core protein assembly modulator (currently Ph2). In particular, we will highlight how the cutting-edge technologies, such as virtual screening, structural biology, and sophisticated medicinal chemistry knowledge, were successfully applied in hit identification, molecular mechanism understanding, and fine-tuning drug-like properties (potency, DMPK, PD, and safety).

The emergence of the COVID-19 pandemic resulted in a large R&D effort to discover direct-acting antiviral therapeutics against SARS-CoV-2. Rapid evolution of new SARS-CoV-2 variants and the presence of multiple other coronaviruses indicates the need for broadly acting antivirals across all coronaviruses. The SARS-CoV-2 3CL protease (3CLpro) is a clinically validated target and is conserved across coronaviruses. Here we will describe our discovery efforts toward oral pan-coronaviral 3CLpro inhibitors.

In a randomized, double-blind Phase 2/3 clinical trial (ABC-201) in severe COVID-19 pneumonia, opaganib (a sphingosine kinase-2 inhibitor) was superior to placebo for time to room air (primary) and secondary endpoints including mortality and time to discharge in patients requiring an FiO2 </=60% (median for the mITT population). Additionally, baseline lymphocyte counts were higher and CRP, D-Dimer, LDH and Ferritin lower in these patients than in those with FiO2>60%. Also, superiority was demonstrated in time to viral clearance, to WHO 1 status, and concomitant administration of remdesivir and corticosteroids in the entire cohort, regardless of FiO2 status.

COVID-19 has led to a global health crisis, and there are still few oral therapeutics available. Herein, we present EDP-235, a novel and potent coronavirus 3C-like protease inhibitor specifically designed for SARS-CoV-2, which is being developed as a once-daily oral antiviral therapy for COVID-19. EDP-235 has demonstrated nanomolar potency preclinically against currently circulating COVID-19 variants as well as other coronaviruses. Moreover, EDP-235 has optimized pharmacokinetic properties with excellent target tissue penetration, including lung, liver, and kidney tissues. The favorable EDP-235 profile suggests the potential as a best-in-class antiviral treatment for SARS-CoV-2 infection. EDP-235 Phase 2 clinical trial will start this year. 

SLR14 is a novel self-stabilized RNA oligonucleotide compound and is a potent agonist of RIG-I, a master regulator of innate immunity in host cells. Activation of RIG-I by binding of SLR14 induces host-directed Interferon signaling cascade that produces IFNs and ISGs for antiviral defense against RNA viruses of different families and biology. SLR14 is a highly selective RIG-I agonist and has demonstrated potent in vitro and in vivo prophylactic and therapeutic antiviral activity against multiple variants of SARS-CoV2, influenza as well as Bunyavirus. RIGImmune is advancing SLR14 towards an IND and clinical development initially against Influenza.

Sustained loss of lipoprotein-like hepatitis B surface antigen (HBsAg) particles is correlated with improved liver outcomes and is a key goal of functional cure. Statin use in chronic hepatitis B (CHB) patients is also associated with improved liver outcomes suggesting a potential role in the perturbation of the lipid composition of HBsAg. In this talk, we will present our data focused on targeting host lipid biosynthesis for treatment of HBV.

The Influenza Endonuclease is an attractive target for stand-alone therapy or in combination offering a fast onset of action and a high genetic barrier to resistance. The talk will illustrate the structure-based optimization of early leads to an advanced candidate with in vivo activity. We demonstrate how the identification and prioritization of a high-throughput cellular assay over a biochemical assay has played a crucial role to accelerate project progression. I will also cover: 

• Investment in chemistry route optimization and high-throughput reliable cellular assay for project acceleration
• Opportunities and challenges of using metal chelators as inhibitors
• Structure-based design

COVID Moonshot is an international open science consortium aiming to discover oral antiviral against SARS-CoV-2, targeting Mpro. In less than 18 months, we went from fragment hits to development candidates now under preclinical evaluation. In my talk, I will discuss Moonshot’s journey, specifically how machine learning has accelerated our design-make-test cycle. I will also discuss our vision for pandemic preparedness and the newly established NIH-funded ASAP antiviral discovery platform.