AVI-4516 for COVID-19

Since the onset of the COVID-19 pandemic, remarkable progress has been made in the development of antiviral therapies for SARS-CoV-2. Several direct-acting antivirals, such as remdesivir, molnupiravir, and nirmatrelvir/ritonavir, offer clinical benefits. These agents have significantly contributed to reducing the viral loads and duration of the illness, as well as the disease’s severity and mortality. However, despite these advances, important limitations remain. The continued emergence of resistant SARS-CoV-2 variants highlights the urgent need for adaptable and durable therapeutic strategies. Therefore, this review aims to provide an updated overview of the main antiviral strategies that are used and the discovery of new drugs against SARS-CoV-2, as well as the therapeutic limitations that have shaped clinical management in recent years. The major challenges include resistance associated with viral mutations, limited treatment windows, and unequal access to treatment. Moreover, there is an ongoing need to identify novel compounds with broad-spectrum activity, improved pharmacokinetics, and suitable safety profiles. Combination treatment regimens represent a promising strategy to increase the efficacy of treating COVID-19 while minimizing the potential for resistance. Ideally, these interventions should be safe, affordable, and easy to administer, which would ensure broad global access and equitable treatment and enable control of COVID-19 cases and preparedness for future threats.

The main protease (M Pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved M Pro inhibition >1000-fold by engaging additional M Pro subsites and using a latent electrophile to engage Cys 145 . Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for AVI-4773 , a rapid reduction in viral titers >1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations >1000× the 90% effective concentration are observed 8 hours after oral dosing for AVI-4773 . AVI-4516 shows minimal inhibition of major cytochrome P450s and human proteases. AVI-4516 also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant M Pro mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical M Pro inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.

The main protease (MPro) of SARS-CoV-2 is crucial for viral replication and is the target of nirmatrelvir (the active ingredient of Paxlovid) and ensitrelvir. The identification of new agents with differentiated pharmacokinetic and drug resistance profiles will increase therapeutic options for COVID-19 patients and bolster pandemic preparedness generally. Starting with a lead-like dihydrouracil chemotype from a large-library docking campaign, we improved MPro inhibition >1,000 fold by engaging additional subsites in the MPro active site, most notably by employing a latent propargyl electrophile to engage the catalytic Cys145. Advanced leads from this series, including AVI 4516 and AVI 4773 show pan-coronavirus antiviral activity in cells, very low clearance in mice, and for AVI 4773 a rapid reduction in viral titers more than a million fold after just three doses, more rapidly and effectively than the approved drugs, nirmatrelvir and ensitrelvir. Both AVI 4516 and AVI 4773 are well distributed in mouse tissues, including brain, where concentrations ten or fifteen-thousand times the EC90, respectively, are observed eight hours after an oral dose. As exemplar of the series, AVI 4516 shows minimal inhibition of major CYP isoforms and human cysteine and serine proteases, likely due to its latent electrophilic warhead. AVI 4516 also exhibits synergy in cellular infection models in combination with the RdRp inhibitor molnupiravir, while related analogs strongly inhibit nirmatrelvir-resistant MPro mutant virus in cells. The in vivo and antiviral properties of this new chemotype are differentiated from existing clinical and pre-clinical MPro inhibitors, and will advance new therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.