Proline Analogues

Chemical Reviews, Год журнала: 2024, Номер 124(13), С. 8130 - 8232

Опубликована: Июнь 28, 2024

Within the canonical repertoire of amino acid involved in protein biogenesis, proline plays a unique role as an presenting modified backbone rather than side-chain. Chemical structures that mimic but introduce changes into its specific molecular features are defined analogues. This review article summarizes existing chemical, physicochemical, and biochemical knowledge about this peculiar family structures. We group analogues from following compounds: substituted prolines, unsaturated fused structures, ring size homologues, heterocyclic, e.g., pseudoproline, bridged proline-resembling overview (1) occurrence nature their chemical synthesis, (2) physicochemical properties including conformation

Язык: Английский

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Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains

Antiviral Research, Год журнала: 2024, Номер 222, С. 105814 - 105814

Опубликована: Янв. 24, 2024

Since the start of SARS-CoV-2 pandemic, search for antiviral therapies has been at forefront medical research. To date, 3CLpro inhibitor nirmatrelvir (Paxlovid®) shown best results in clinical trials and greatest robustness against variants. A second protease inhibitor, ensitrelvir (Xocova®), developed. Ensitrelvir, currently Phase 3, was approved Japan under emergency regulatory approval procedure November 2022, is available since March 31, 2023. One limitations use monotherapies emergence resistance mutations. Here, we experimentally generated mutants resistant to vitro following repeating passages presence both antivirals. For molecules, demonstrated a loss sensitivity vitro. Using Syrian golden hamster infection model, showed that M49L mutation, multi-passage strain, confers high level vivo resistance. Finally, identified recent increase prevalence M49L-carrying sequences, which appears be associated with multiple repeated events may related Xocova® country 2022. These highlight strategic importance genetic monitoring circulating strains ensure treatments administered retain their full effectiveness.

Язык: Английский

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SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Год журнала: 2024, Номер 31(4), С. 632 - 657

Опубликована: Апрель 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Язык: Английский

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Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents

Biomolecules, Год журнала: 2024, Номер 14(7), С. 797 - 797

Опубликована: Июль 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Язык: Английский

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Structural Basis for Coronaviral Main Proteases Inhibition by the 3CLpro Inhibitor GC376

Journal of Molecular Biology, Год журнала: 2024, Номер 436(6), С. 168474 - 168474

Опубликована: Фев. 2, 2024

Язык: Английский

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Proof-of-concept studies with a computationally designed M ^pro inhibitor as a synergistic combination regimen alternative to Paxlovid

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(17)

Опубликована: Апрель 15, 2024

As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug interactions can occur Paxlovid patients who are taking other medications by CYP4503A4, particularly transplant or otherwise immunocompromised most at risk development severe symptoms. Developing an alternative improved pharmacological properties critical these By using computational structure-guided approach, we were able optimize 100 250 μM screening hit potent nanomolar inhibitor lead compound, Mpro61. In study, further evaluate Mpro61 as starting examination its mode binding M . vitro profiling established lack off-target effects, inhibition, well potential synergy currently approved alternate antiviral, molnupiravir. Development subsequent testing capsule formulation oral dosing in B6-K18-hACE2 mice demonstrated favorable properties, efficacy, molnupiravir, complete recovery from challenge SARS-CoV-2, establishing promising preclinical candidate.

Язык: Английский

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Emerging SARS-CoV-2 Resistance After Antiviral Treatment

JAMA Network Open, Год журнала: 2024, Номер 7(9), С. e2435431 - e2435431

Опубликована: Сен. 25, 2024

Importance Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this arises and its association with posttreatment virologic rebound is not well understood. Objective To examine the prevalence of emergent antiviral after nirmatrelvir treatment rebound. Design, Setting, Participants This cohort study enrolled outpatient adults acute COVID-19 infection from May 2021 October 2023. were divided into those who received therapy did not. The was conducted at a multicenter health care system Boston, Massachusetts. Exposure Treatment regimen, including none, remdesivir. Main Outcomes Measures primary outcome resistance, defined as detection mutations, which present baseline, previously associated decreased efficacy, emerged during or completion participant’s treatment. Next-generation sequencing used detect low frequency down 1% total viral population. Results Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) included. Compared 63 untreated individuals, 79 older more commonly immunosuppressed. After RNA participants’ anterior nasal swabs, detected 9 individuals (11.4%) compared 2 (3.2%) ( P = .09). Among treated immunosuppressed had highest emergence (5 22 [22.7%]), significantly greater than (2 [3.1%]) .01). Similar rates found (3 23 [13.0%]) vs (6 [10.7%]) .86). Most these (10 11 [90.9%]) frequencies (<20% population) reverted wild type subsequent time points. Emerging remdesivir only 14 [14.3%]) but similarly transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence increased United States authorization nirmatrelvir. Conclusions Relevance In participants, treatment-emergent detected, especially However, generally transient nature, suggesting risk for spread community current variants drug usage patterns.

Язык: Английский

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Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction

Virology, Год журнала: 2025, Номер 604, С. 110394 - 110394

Опубликована: Янв. 11, 2025

Язык: Английский

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Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Авг. 8, 2022

Abstract Vaccines and drugs have helped reduce disease severity blunt the spread of SARS-CoV-2. However, ongoing virus transmission, continuous evolution, increasing selective pressures potential to yield viral variants capable resisting these interventions. Here, we investigate susceptibility natural main protease (M pro /3CL ) SARS-CoV-2 inhibitors. Multiple single amino acid changes in M confer resistance nirmatrelvir (the active component Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different mutation profile. Importantly, phylogenetic analyses indicate that several resistant pre-existed introduction into human population are spreading. These results encourage monitoring development inhibitors other antiviral with mechanisms action profiles for combinatorial therapy. One Sentence Summary Resistance inhibitor drugs, (Paxlovid) exists population.

Язык: Английский

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Contribution of the catalytic dyad of SARS-CoV-2 main protease to binding covalent and noncovalent inhibitors

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(7), С. 104886 - 104886

Опубликована: Июнь 3, 2023

The effect of mutations the catalytic dyad residues SARS-CoV-2 main protease (MProWT) on thermodynamics binding covalent inhibitors comprising nitrile [nirmatrelvir (NMV), NBH2], aldehyde (GC373), and ketone (BBH1) warheads to MPro is examined together with room temperature X-ray crystallography. When lacking nucleophilic C145, NMV ∼400-fold weaker corresponding 3.5 kcal/mol 13.3 °C decrease in free energy (ΔG) thermal stability (Tm), respectively, relative MProWT. H41A mutation results a 20-fold increase dissociation constant (Kd), 1.7 1.4 decreases ΔG Tm, respectively. Increasing pH from 7.2 8.2 enhances MProH41A, whereas no significant change observed Structures four inhibitor complexes MPro1-304/C145A show that active site geometries are nearly identical MProWT sulfur C145 positioned react or carbonyl carbon. These support two-step mechanism for formation complex involving an initial non-covalent followed by attack thiolate anion warhead Noncovalent ensitrelvir (ESV) exhibits affinity similar but differs its thermodynamic signature NMV. ESV MProC145A also significant, smaller, Kd

Язык: Английский

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