Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19

Med, Год журнала: 2024, Номер 5(1), С. 42 - 61.e23

Опубликована: Янв. 1, 2024

BackgroundOral antiviral drugs with improved potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks rebound, drug-drug interactions, emerging resistance.MethodsOlgotrelvir (STI-1558) is designed as a next-generation targeting SARS-CoV-2 main protease (Mpro), an essential enzyme replication, human cathepsin L (CTSL), key entry into host cells.FindingsOlgotrelvir highly bioavailable oral prodrug that converted plasma its active form, AC1115. The dual mechanism action olgotrelvir AC1115 was confirmed by activity inhibition assays co-crystal structures Mpro CTSL. displayed inhibiting replication all tested variants cell culture systems. Olgotrelvir also inhibited viral cells using Spike-mediated pseudotypes In K18-hACE2 transgenic mouse model SARS-CoV-2-mediated disease, significantly reduced virus load lungs, prevented body weight loss, cytokine release lung pathologies. demonstrated potent against nirmatrelvir-resistant E166 mutants. showed enhanced bioavailability animal models humans significant exposure without ritonavir. phase I studies (ClinicalTrials.gov: NCT05364840 NCT05523739), favorable profile activity.ConclusionsOlgotrelvir inhibitor CTSL high standalone candidate COVID-19.FundingFunded Sorrento Therapeutics.

Язык: Английский

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Preparing for the next viral threat with broad-spectrum antivirals

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(11)

Опубликована: Май 31, 2023

There is a large global unmet need for the development of countermeasures to combat hundreds viruses known cause human disease and establishment therapeutic portfolio future pandemic preparedness. Most approved antiviral therapeutics target proteins encoded by single virus, providing narrow spectrum coverage. This, combined with slow pace high cost drug development, limits scalability this direct-acting (DAA) approach. Here, we summarize progress challenges in broad-spectrum antivirals that either viral elements (proteins, genome structures, lipid envelopes) or cellular proviral factors co-opted multiple via newly discovered compounds repurposing drugs. These strategies offer new means developing against both existing emerging threats complement DAAs.

Язык: Английский

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Combination regimen of nirmatrelvir/ritonavir and molnupiravir for the treatment of persistent SARS-CoV-2 infection: A case report and a scoping review of the literature

International Journal of Infectious Diseases, Год журнала: 2023, Номер 133, С. 53 - 56

Опубликована: Май 5, 2023

Immunocompromised patients still experience unpredictable courses of COVID-19, despite that effective vaccines and drugs against SARS-CoV-2 are now available. Antiviral combination regimens may have a role in infection immunocompromised hosts, but current knowledge is limited. We describe the case 73-year-old Italian man affected by follicular lymphoma with persistent who was successfully treated co-administration oral antivirals (10-day molnupiravir nirmatrelvir/ritonavir). The therapy well tolerated both from clinical biochemical standpoint, no signs toxicity. also performed scoping review, to sum up available on combined antiviral including remdesivir, molnupiravir, or nirmatrelvir/ritonavir. Pending further studies larger cohorts patients, our report consistent pre-clinical data, supporting possible use selected difficult-to-treat COVID-19 cases.

Язык: Английский

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SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Future Pharmacology, Год журнала: 2023, Номер 3(1), С. 80 - 107

Опубликована: Янв. 9, 2023

While the COVID-19 pandemic seems to be on its decline, unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not underestimated threat. These along with preparedness, ask for an alert identification new drugs optimization existing as therapeutic treatment options this potential future diseases. Mpro inhibitors were identified early potent drug candidates against coronaviruses, since they target viable processing machinery within virus, i.e., main protease that cleaves polyproteins encoded by viral RNA into functional proteins. Different strategies, including reversible irreversible inhibition well allosteric inhibitors, mostly from repurposing endeavors, have been explored design SARS-CoV-2 antivirals. Ambitious screening efforts uttered outstanding chemical structural diversity, which has led half dozen lead compounds being currently clinical trials emergency FDA approval ritonavir-boosted nirmatrelvir therapeutic. This comprehensive analysis achieved inhibitor diversity sorted irreversible, reversible, binders, discussion emerging resistance reports possible evasion is aimed at stimulating continuing efforts.

Язык: Английский

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Achieving Optimal Health With Host‐Directed Therapies (HDTs) in Infectious Diseases—A New Horizon

Advanced Therapeutics, Год журнала: 2024, Номер unknown

Опубликована: Сен. 18, 2024

Abstract Host‐directed therapies (HDTs) have emerged as a promising strategy to combat viral infections by modifying host factors and immune responses restrict replication improve patient outcomes. This review summarizes the latest advances future potential of HDTs in antiviral therapy. With developments genomics proteomics, new targets essential for been identified. Gene‐editing tools, such CRISPR‐Cas9, enable precise manipulation genes linked processes, paving way innovative HDTs. Emerging approaches, including RNA interference interference, further demonstrate specifically modify inhibit replication. Additionally, probiotics are being explored their capacity enhance modulate gut microbiota, offering natural safe method boosting defenses. Despite these advancements, significant challenges remain, particularly deciphering complex host–virus interactions ensuring safety efficacy therapies. Continued research clinical evaluation realize full provides comprehensive overview current HDT strategies, emphasizing promise shaping interventions.

Язык: Английский

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Recent Advances on Targeting Proteases for Antiviral Development

Viruses, Год журнала: 2024, Номер 16(3), С. 366 - 366

Опубликована: Фев. 27, 2024

Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible causing diseases humans, like West Nile virus (WNV) recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding mechanisms behind blocking protease’s function is pivotal development antiviral drugs therapeutical strategies. Apart from directly inhibiting protease, usually by targeting its active site, have been explored to impair activity, such as inducing protein aggregation, allosteric sites or degradation cellular proteasomes, which be extremely valuable when considering emerging drug-resistant strains. In this review, we aim discuss advances on a broad range inhibitors, therapies molecular approaches inactivation degradation, giving insight different possible strategies against class target.

Язык: Английский

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A unifying model to explain frequent SARS-CoV-2 rebound after nirmatrelvir treatment and limited prophylactic efficacy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 28, 2024

Abstract In a pivotal trial (EPIC-HR), 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days symptoms onset), decreased hospitalization and death by 89.1% nasal viral load 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis trial, frequent rebound has been observed subsequent cohorts. We develop mathematical model capturing viral-immune dynamics nirmatrelvir pharmacokinetics that recapitulates loads from this another clinical (PLATCOV). Our results suggest nirmatrelvir’s vivo potency is significantly lower than vitro assays predict. According our model, maximally potent agent would reduce the approximately 3.5 logs at 5 days. The identifies earlier initiation shorter treatment duration are key predictors post-treatment rebound. Extension 10 for Omicron variant vaccinated individuals, rather increasing dose or dosing frequency, predicted incidence significantly.

Язык: Английский

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The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance

Antiviral Research, Год журнала: 2024, Номер 225, С. 105840 - 105840

Опубликована: Март 2, 2024

Host targeting antiviral drugs (HTA) are directed against cellular mechanisms which can be exploited by viruses. These essential for viral replication, because missing functions cannot compensated the virus. However, this assumption needs experimental proof. Here we compared HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities SARS-CoV-2. During serial passage δ-B1.617.2 adaptation all DAAs occurred, while inhibitory capacity ZMN was not altered. Known single nucleotide polymorphisms (SNPs) responsible partial resistances were found RDV, NTV and PAX. Additionally, high mutagenic potential MPV confirmed decreased efficacies first time. Reduced DAA efficacy did alter ZMN. results show that confers a barrier towards development resistance has act partially DAA-insensitive

Язык: Английский

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Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among first reported inhibitors was peptidomimetic α-ketoamide 13b, whose cocrystal structure with paved way for multiple lead-finding studies. We established structure-activity relationships 13b series modifying residues at P1', P3, and P4 sites. Guided structures, we reduced P1' substituent size better fill pocket added fluorine pyridone ring, enabling new hydrogen bond Gln189 in P3. 22 novel analogues, 6d 12d inhibited IC50s of 110 nM 40 nM, improving potency up 9.5-fold. Compound had pronounced antiviral activity an EC50 1.6 μM stable plasma microsomes. study illustrates potential structure-based design systematically improve α-ketoamides.

Язык: Английский

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DHODH inhibitors: What will it take to get them into the clinic as antivirals?

Antiviral Research, Год журнала: 2025, Номер 236, С. 106099 - 106099

Опубликована: Фев. 10, 2025

The emergence of new human viruses with epidemic or pandemic potential has reaffirmed the urgency to develop effective broad-spectrum antivirals (BSAs) as part a strategic framework for prevention and preparedness. To this end, host nucleotide metabolic pathway been subject intense investigation in search host-targeting agents (HTAs) BSA activity. In particular, dihydroorotate dehydrogenase (hDHODH), rate-limiting enzyme de novo pyrimidine biosynthetic pathway, identified preferential target HTAs. Viral replication fact relies on cellular replenishment, making hDHODH an ideal HTA target. depletion pool that ensues pharmacological inhibition activity elicits through three distinct mechanisms: it blocks viral DNA RNA synthesis; activates effector mechanisms innate antiviral response; mitigates virus-induced inflammatory response. However, despite spectacular results obtained vitro, inhibitors examined mono-drug therapies animal models infections clinical trials have produced disappointing levels overall efficacy. overcome inherent limitation, strategies based multi-drug combination treatments should be considered enable efficacy hDHODH-targeted therapies. Here, we review state-of-the-art applications inhibitors, discuss challenges emerged from their testing consider how they might addressed advance development treatment diseases.

Язык: Английский

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