ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown
Published: April 14, 2025
Language: Английский
European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115772 - 115772
Published: Aug. 28, 2023
Language: Английский
Citations
52
Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(7), P. 4468 - 4490
Published: March 24, 2023
The current monkeypox outbreaks during the COVID-19 pandemic have reignited interest in orthopoxvirus antivirals. Monkeypox belongs to Orthopoxvirus genus of Poxviridae family, which also includes variola virus, vaccinia and cowpox virus. Two orally bioavailable drugs, tecovirimat brincidofovir, been approved for treating smallpox infections. Given their human safety profiles vivo antiviral efficacy animal models, both drugs recommended treat infection. To facilitate development additional antivirals, we summarize activity, mechanism action, resistance This perspective covers direct-acting host-targeting antivirals with an emphasis on drug candidates showing models. We hope speed discovery by providing medicinal chemists insights into prioritizing proper targets hits further development.
Language: Английский
Citations
47
Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(5), P. 663 - 663
Published: April 28, 2023
In spite of the increasing number biologics license applications, development covalent inhibitors is still a growing field within drug discovery. The successful approval some protein kinase inhibitors, such as ibrutinib (BTK inhibitor) and dacomitinib (EGFR inhibitor), very recent discovery for viral proteases, boceprevir, narlaprevir, nirmatrelvir, represent new milestone in development. Generally, formation bonds that target proteins can offer drugs diverse advantages terms selectivity, resistance, administration concentration. most important factor electrophile (warhead), which dictates reactivity, type binding (i.e., reversible or irreversible) be modified/optimized through rational designs. Furthermore, are becoming more common proteolysis, targeting chimeras (PROTACs) degrading proteins, including those currently considered to ‘undruggable’. aim this review highlight current state inhibitor development, short historical overview examples applications PROTAC technologies treatment SARS-CoV-2 virus.
Language: Английский
Citations
45
Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(2), P. 217 - 217
Published: Feb. 2, 2024
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms action some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. most effective drug approved date for treatment is PaxlovidTM, which combination two protease inhibitors, nirmatrelvir ritonavir. Nirmatrelvir reversible covalent peptidomimetic inhibitor main (Mpro) SARS-CoV-2, enzyme plays crucial role reproduction. In this combination, ritonavir serves as pharmacokinetic enhancer, it irreversibly inhibits cytochrome CYP3A4 responsible rapid metabolism nirmatrelvir, thereby increasing half-life bioavailability nirmatrelvir. tutorial review, we summarize development pharmaceutical chemistry aspects Paxlovid, covering evolution warhead design, synthesis mechanism well its inhibition mechanism. efficacy Paxlovid novel virus mutants also overviewed.
Language: Английский
Citations
17
Clinical Microbiology Reviews, Journal Year: 2024, Volume and Issue: 37(2)
Published: May 21, 2024
SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy those often remains controversial or compromised by viral evolution. Uncertainties still persist regarding best therapies for high-risk patients, drug pipeline is suffering fatigue shortage funding. In this article, we review antiviral activity, mechanism action, pharmacokinetics, safety therapies. Additionally, summarize evidence from randomized controlled trials on various antivirals discuss unmet needs which should be addressed.
Language: Английский
Citations
13
Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(1), P. 68 - 68
Published: Jan. 4, 2024
The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone fight against malignancies. However, majority clinically employed inhibitors are monoclonal antibodies (mAbs) with several limitations, such as poor oral bioavailability and immune-related adverse effects (irAEs). Another major limitation is restriction efficacy mAbs to subset patients, which triggered extensive research efforts identify alternative approaches targeting checkpoints aiming overcome restricted mAbs. This comprehensive review aims explore cutting-edge developments checkpoints, focusing on both small molecule- peptide-based approaches. By delving into drug discovery platforms, we provide insights diverse strategies optimize molecules peptides checkpoints. In addition, discuss recent advances nanomaterials carriers, providing basis for development platforms immunotherapy. Ongoing focused peptide-inspired agents paves way developing orally bioavailable next-generation immunotherapies.
Language: Английский
Citations
10
Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8130 - 8232
Published: June 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
Language: Английский
Citations
10
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: Feb. 1, 2025
SARS-CoV-2 main protease, Mpro, is responsible for processing the viral polyproteins into individual proteins, including protease itself. Mpro a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component Paxlovid). Resistance mutants identified clinically and in passage assays contain combination site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding enzymatic activity, non-active P252L, T21I, L50F), restore fitness replication. To probe role rescue, here we use an triple mutant (L50F/E166A/L167F) that confers drug resistance with level similar to wild-type. By comparing peptide full-length protein substrates, demonstrate substrate involves more than residues site. Particularly, L50F other can enhance dimer-dimer interactions help place nsp5-6 at enzyme catalytic center. The structural activity data L50F, L50F/E166A/L167F, others underscore importance considering whole studying interactions, offers important insights function, development, design.
Language: Английский
Citations
1
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: Feb. 13, 2025
The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents systematic design quinoline-containing papain-like protease (PLpro) inhibitors as potential antiviral drug candidates. By leveraging recently discovered Val70Ub binding site in PLpro, we designed a series quinoline analogs demonstrating potent PLpro inhibition and activity. Notably, X-ray crystal structures 6 lead compounds reveal that 2-aryl substitution can occupy either expected or BL2 groove flipped orientation. vivo Jun13296 exhibits favorable pharmacokinetic properties against nirmatrelvir-resistant mutants. In mouse model infection, treatment with significantly improves survival, reduces body weight loss lung viral titers, prevents tissue damage. These results underscore promising candidates, instilling hope for future treatment. inhibitor, Jun13296, displays efficacy infection inhibits mutants, rendering it candidate.
Language: Английский
Citations
1
European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 259, P. 115667 - 115667
Published: July 19, 2023
Language: Английский
Citations
20