An official website of the United States government
Abstract Purpose of the ReviewSARS-CoV-2 undergoes genetic mutations like many other viruses. Some mutations lead to the emergence of new Variants of Concern (VOCs), affecting transmissibility, illness severity, and the effectiveness of antiviral drugs. Continuous monitoring and research are crucial to comprehend variant behavior and develop effective response strategies, including identifying mutations that may affect current drug therapies. Recent FindingsAntiviral therapies such as Nirmatrelvir and Ensitrelvir focus on inhibiting 3CLpro, whereas Remdesivir, Favipiravir, and Molnupiravir target nsp12, thereby reducing the viral load. However, the emergence of resistant mutations in 3CLpro and nsp12 could impact the efficiency of these small molecule drug therapeutics. SummaryThis manuscript summarizes mutations in 3CLpro and nsp12, which could potentially reduce the efficacy of drugs. Additionally, it encapsulates recent advancements in small molecule antivirals targeting SARS-CoV-2 viral proteins, including their potential for developing resistance against emerging variants.
more »
« less
Intracellular interactions shape antiviral resistance outcomes in poliovirus via eco-evolutionary feedback
Resistance evolution can undermine antiviral treatment. However, targeting antivirals to shared viral proteins could inhibit resistance evolution if susceptible viruses sensitize resistant ones during cellular coinfection. Pocapavir, a poliovirus capsid inhibitor, uses this sociovirological interference strategy. While susceptible viruses substantially suppress pocapavir resistance in cell culture, a pocapavir clinical trial found widespread resistance and limited clearance time improvements in treated participants. Here, to reconcile these findings, we present an intrahost eco-evolutionary model of pocapavir-treated poliovirus, which reproduces both in vitro interference and clinical resistance evolution. In the short term, high densities of susceptible viruses sensitize resistant ones, mirroring cell culture results. However, over multiple replication cycles, pocapavir’s high potency collapses viral density, reducing coinfection and enabling resistance evolution, as observed clinically. Because resistance suppression relies on coinfection, enhancing susceptible virus survival could offer therapeutic advantages. Counterintuitively, we demonstrate that lessening antiviral potency can increase coinfection, limiting resistance while also maintaining low viral load. These findings suggest that antivirals relying on viral intracellular interactions must balance immediate neutralization with preserving future coinfection for sustained inhibition. Explicitly considering the eco-evolutionary feedback encompassing viral density, shared phenotypes and absolute fitness provides new insights for effective therapy design and illuminates viral evolutionary dynamics more broadly.
more »
« less
- Award ID(s):
- 2142718
- PAR ID:
- 10661745
- Publisher / Repository:
- Nature Portfolio
- Date Published:
- Journal Name:
- Nature Ecology & Evolution
- ISSN:
- 2397-334X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Marine microbes are important in biogeochemical cycling, but the nature and magnitude of their contributions are influenced by their associated viruses. In the presence of a lytic virus, cells that have evolved resistance to infection have an obvious fitness advantage over relatives that remain susceptible. However, susceptible cells remain extant in the wild, implying that the evolution of a fitness advantage in one dimension (virus resistance) must be accompanied by a fitness cost in another dimension. Identifying costs of resistance is challenging because fitness is context‐dependent. We examined the context dependence of fitness costs in isolates of the picophytoplankton genusMicromonasand their co‐occurring dsDNA viruses using experimental evolution. After generating 88 resistant lineages from two ancestralMicromonasstrains, each challenged with one of four distinct viral strains, we found resistance led to a 46% decrease in mean growth rate under high irradiance and a 19% decrease under low. After a year in culture, the experimentally selected lines remained resistant, but fitness costs had attenuated. Our results suggest that the cost of resistance inMicromonasis dependent on environmental conditions and the duration of population adaptation, illustrating the dynamic nature of fitness costs of viral resistance among marine protists.more » « less
-
Kretzschmar, Mirjam E. (Ed.)Background Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials. Methods and findings A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates ( p -value < 0.001). The mean decay rates were 1.17 d −1 (95% CI: 1.06 to 1.27 d −1 ), 0.777 d −1 (0.716 to 0.838 d −1 ), and 0.450 d −1 (0.378 to 0.522 d −1 ) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. Conclusions In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.more » « less
-
The antiviral remdesivir has been approved by regulatory bodies such as the European Medicines Agency (EMA) and the US Food and Drug administration (FDA) for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose–activity relationships. Here, we employ a computational model that allows drug efficacy predictions based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby describe a drug regimen that may select for resistance. Our results differ from predictions using prodrug dose–response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in the lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend more clinical trials with dosing regimens that substantially increase the levels of RDV-TP and/or pair remdesivir with companion antivirals.more » « less
-
The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic candidates, particularly for combating newly emergent viral threats. The innate immune system features a sustained capability to combat pathogens through production of antimicrobial peptides (AMPs); however, these AMPs have shortcomings that can preclude clinical use. The essential functional features of AMPs have been recapitulated by peptidomimetic oligomers, yielding effective antibacterial and antifungal agents. Here, we show that a family of AMP mimetics, called peptoids, exhibit direct antiviral activity against an array of enveloped viruses, including the key human pathogens Zika, Rift Valley fever, and chikungunya viruses. These data suggest that the activities of peptoids include engagement and disruption of viral membrane constituents. To investigate how these peptoids target lipid membranes, we used liposome leakage assays to measure membrane disruption. We found that liposomes containing phosphatidylserine (PS) were markedly sensitive to peptoid treatment; in contrast, liposomes formed exclusively with phosphatidylcholine (PC) showed no sensitivity. In addition, chikungunya virus containing elevated envelope PS was more susceptible to peptoid-mediated inactivation. These results indicate that peptoids mimicking the physicochemical characteristics of AMPs act through a membrane-specific mechanism, most likely through preferential interactions with PS. We provide the first evidence for the engagement of distinct viral envelope lipid constituents, establishing an avenue for specificity that may enable the development of a new family of therapeutics capable of averting the rapid development of resistance.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript
- Journal Article:
- https://doi.org/10.1038/s41559-025-02926-x
