The COVID-19 pandemic (2019-2023) demonstrated the need for safe and effective, stockpiled broad-spectrum antiviral drugs to suppress unexpected viral outbreaks. The inability of the pharmaceutical industry to create such a therapeutic in the 6 years since the onset of COVID-19 demonstrates antiviral drug development must undergo a paradigm shift for this to occur. AI-based target and medicinal chemistry discovery platforms such as GALILEO and its geometric graph convolutional network tool ChemPrint, which we recently published, hold promise in accelerating and reimagining the drug development process. GALILEO identified the Thumb-1 site (an allosteric subdomain of the viral RNA polymerase) to be structurally conserved across numerous viral species and MDL-001 (an orally available therapeutic with a favorable pharmacokinetics and safety profile in humans) to be a potent inhibitor thereof. Published preclinical proof-of-concept studies demonstrated MDL-001 as a first-in-class broad-spectrum antiviral drug. This study leverages 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. Specifically, ChemPrint’s one-shot predictions identified 12 NCEs with predicted affinity to Thumb-1 and significantly reduced, or no, affinity to MDL-001’s original target. In vitro bioassays demonstrated a 100% hit rate, with all 12 NCEs having antiviral activity against Hepatitis C Virus (HCV) and/or human Coronavirus 229E. In vitro studies also demonstrated reduced activity of 800-fold to greater than 15,000-fold relative to MDL-001’s originally designed mechanism of action (MoA). In Tanimoto similarity plots, the 12 NCEs lacked chemical relatedness to known antiviral drugs, including MDL-001 (average Tanimoto coefficient: 0.38) and Beclabuvir, (average Tanimoto coefficient: 0.13) a HCV Thumb-1 ligand that lacks broad-spectrum activity. This study showcases GALILEO’s ability to generate vast NCE libraries and ChemPrint’s extrapolative capabilities to discover large, potent NCE libraries of compounds, specific to a complex target that are novel to known chemistry at high hit-rates.

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIV mac 239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after respiratory clearance. Despite global vaccination and existing antiviral treatments, variants of concern are still emerging and circulating. Of note, new Omicron BA.5 sublineages both increasingly evade neutralizing antibodies and demonstrate an increased preference for entry via the endocytic entry route. Alternative to direct-acting antivirals, host-directed therapies interfere with host mechanisms hijacked by viruses, and enhance cell-mediated resistance with a reduced likelihood of drug resistance development. Here, we demonstrate that the autophagy-blocking therapeutic berbamine dihydrochloride robustly prevents SARS-CoV-2 acquisition by human intestinal epithelial cells via an autophagy-mediated BNIP3 mechanism. Strikingly, berbamine dihydrochloride exhibited pan-antiviral activity against Omicron subvariants BA.2 and BA.5 at nanomolar potency, providing a proof of concept for the potential for targeting autophagy machinery to thwart infection of current circulating SARS-CoV-2 subvariants. Furthermore, we show that autophagy-blocking therapies limited virus-induced damage to intestinal barrier function, affirming the therapeutic relevance of autophagy manipulation to avert the intestinal permeability associated with acute COVID-19 and post-COVID-19 syndrome. Our findings underscore that SARS-CoV-2 exploits host autophagy machinery for intestinal dissemination and indicate that repurposed autophagy-based antivirals represent a pertinent therapeutic option to boost protection and ameliorate disease pathogenesis against current and future SARS-CoV-2 variants of concern.

Throughout the SARS-CoV-2 pandemic, the use of botanical dietary supplements in the United States has increased, yet their safety and efficacy against COVID-19 remains underexplored. The Quave Natural Product Library is a phylogenetically diverse collection of botanical and fungal natural product extracts including popular supplement ingredients. Evaluation of 1867 extracts and 18 compounds for virus spike protein binding to host cell ACE2 receptors in a SARS-CoV-2 pseudotyped virus system identified 310 extracts derived from 188 species across 76 families (3 fungi, 73 plants) that exhibited ≥ 50% viral entry inhibition activity at 20 µg/mL. Extracts exhibiting mammalian cytotoxicity > 15% and those containing cardiotoxic cardiac glycosides were eliminated. Three extracts were selected for further testing against four pseudotyped variants and infectious SARS-CoV-2 and were then further chemically characterized, revealing the potent (EC50 < 5 µg/mL) antiviral activity of Solidago altissima L. (Asteraceae) flowers and Pteridium aquilinum (L.) Kuhn (Dennstaedtiaceae) rhizomes.
© 2023. The Author(s).

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.