Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC₅₀ = 0.13 μM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC₅₀ = 0.44 μM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.

2024-04-01·European Journal of Medicinal Chemistry

Discovery of novel polyheterocyclic neuraminidase inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone

Article

作者: Zhong, Zhi Jian ; Cheng, Li Ping ; Shang, Lin Lin

Inspired by our earlier findings regarding neuraminidase (NA) inhibitors interacting with 150-cavity or 430-cavity of NA, sixteen novel polyheterocyclic NA inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone were designed and synthesized based on the lead compound ZINC13401480. Of the synthesized compounds, compound N5 targeting 150-cavity exerts the best inhibitory activity against the wild-type H5N1 NA, with IC₅₀ value of 0.14 μM, which is superior to oseltamivir carboxylate (OSC) (IC₅₀ = 0.31 μM). Compound N10 targeting 430-cavity exhibits the best activity against the H5N1-H274Y mutant NA. Although the activity of N10 is comparable to that of OSC for wild-type H5N1 inhibition, it is approximately 60-fold more potent than OSC against the H274Y mutant, suggesting that it is not easy for the virus to develop drug resistance and is attractive for drug development. N10 (EC₅₀ = 0.11 μM) also exhibits excellent antiviral activity against H5N1, which is superior to the positive control OSC (EC₅₀ = 1.47 μM). Molecular docking study shows that the occupation of aromatic fused rings and oxadiazole moiety at the active site and the extension of the substituted phenyl to the 150-cavity or 430-cavity make great contributions to the good potency of this series of polyheterocyclic NA inhibitors. Some advancements in the discovery of effective target-specific NA inhibitors in this study may offer some assistance in the development of more potent anti-influenza drugs.

2024-03-01·HemaSphere

Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia‐positive lymphoid leukemia to tyrosine kinase inhibitors

Article

作者: Pastorczak, Agata ; Winiarska, Magdalena ; Fidyt, Klaudyna ; Janowska, Martyna ; Szczygiel, Kacper ; Hunia, Jaromir ; Bielecki, Maksymilian ; Patkowska, Elzbieta ; Firczuk, Malgorzata ; Madzio, Joanna ; Bajor, Malgorzata ; Stoklosa, Tomasz ; Dabkowska, Agnieszka ; Komorowski, Lukasz

AbstractBreakpoint cluster region‐Abelson (BCR::ABL1) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia‐positive (Ph+) B‐cell acute lymphoblastic leukemia (B‐ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+ B‐ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B‐ALL. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B‐ALL cells, particularly in combination with other drugs. Here, we present that peroxiredoxin‐1 (PRDX1), one of the enzymes of the TXN system, is upregulated in Ph+ lymphoid as compared to Ph+ myeloid cells. PRDX1 knockout negatively affects the viability of Ph+ B‐ALL cells and sensitizes them to TKIs. Analysis of global gene expression changes in imatinib‐treated, PRDX1‐deficient cells revealed that the nonhomologous end‐joining (NHEJ) DNA repair is a novel vulnerability of Ph+ B‐ALL cells. Accordingly, PRDX1‐deficient Ph+ B‐ALL cells were susceptible to NHEJ inhibitors. Finally, we demonstrated the potent efficacy of a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors against Ph+ B‐ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph+ B‐ALL.

项与 NHE inhibitors (Medicure) 相关的新闻（医药）

2023-04-13

·BioSpace

Peel Therapeutics Describes Excessive NETosis Induction in Long COVID

Peer-reviewed study offers first description of ongoing NETosis induction in Long COVID; provides insights into pathogenesis and can serve as a surrogate marker for persistent pathology Research emphasizes need to explore neutrophil-targeted therapies in acute and chronic COVID-19 SALT LAKE CITY, April 13, 2023 /PRNewswire/ -- Peel Therapeutics, an evolutionary-inspired, clinical-stage biotech company, announced research conducted by the company has been published in The Journal of Thrombosis and Haemostasis. The study, NETosis Induction Reflects COVID-19 Severity and Long COVID: Insights from a Two-Center Patient Cohort Study in Israel, evaluated the ability of blood from Israeli patients with Long COVID to induce neutrophil extracellular traps (NETs) as a marker of ongoing inflammation. NETs are sticky webs of DNA released by activated immunes cells that contribute to immunothrombosis (mini-clots) and fibrosis. Peel scientists also correlated NETosis potential with acute disease severity in COVID-19. The study concluded that NET inhibitors may be a possible treatment approach for COVID-19 and recommended additional research to confirm findings. Peel Therapeutics is developing first-in-class Neutrophil Targeting Peptides (NTPs) – originating from natural NET inhibitors in newborns – to block inflammation leading to immunothrombosis and fibrosis. In this study, Peel researchers examined NETs among people with and without COVID-19 and measured NET induction during and after infection. The study concluded that increased NETosis induction can be detected in people with Long COVID, offering insight into the potential uses of NTPs and other NET inhibitors for the treatment of Long COVID. The study included 177 patients from 2 Israeli hospitals with acute COVID-19 infection (mild/moderate or severe/critical) or convalescent COVID-19 (recovered or Long COVID), along with 54 non-COVID controls. People who experienced symptoms of Long COVID maintained higher NETosis induction compared to recovered convalescent patients. Dr. Kimberly Martinod, Assistant Professor in Cardiovascular Sciences at KU Leuven, runs a NET research laboratory that studies clotting and fibrosis in heart failure and is co-author on the paper. Dr. Martinod remarked, "Measuring NETs in blood samples is challenging. The Peel team quantified the ability of patient blood to form NETs instead of measuring fragments of NETs which can be complicated by their rapid degradation – especially in COVID-19 where this is unbalanced. This study demonstrates the increased ability of blood from patients with acute and ongoing COVID-19 to induce NETs in healthy neutrophils. This reflects ongoing inflammation that may trigger excessive NET release, even weeks after the initial infection has cleared." Peel CEO and Co-founder, Dr. Joshua Schiffman, stated, "This study offers a new target for COVID patients suffering from ongoing inflammation. The potential use of our NTPs in acute and chronic COVID further validates Peel's ability to unlock evolutionary biology for cancer and inflammation. Our preclinical research lays the groundwork for scientists and clinicians to understand NTP's potential to treat inflammatory diseases, improve health outcomes, and in this case, offer hope to patients with Long COVID." The study can be accessed via the Journal of Thrombosis and Haemostasis. About Peel Therapeutics Peel Therapeutics is an evolutionary-inspired, clinical-stage biotech company that engineers nature better than evolution intended. Our scientists search for nature's super abilities where evolutionary biology accomplished the inconceivable in preventing or defeating disease. We then apply drug development expertise to rapidly translate this evolutionary biology into medicines. The company is advancing a therapeutic pipeline to treat a spectrum of devastating conditions, with a near-term focus on cancer and inflammation. At Peel Therapeutics, we push the limits of biology to develop highly effective and safe medicines for patients. "Peel" is the Hebrew word for elephant, our company originates from the natural cancer resistance found in elephants.

免疫疗法临床结果

100 项与 NHE inhibitors (Medicure) 相关的药物交易

登录后查看更多信息