Gold nanoparticles (AuNPs) have shown remarkable potential for vaccine development, but the influence of the size and shape of nanoparticles modulating the T-cell-dependent carbohydrate antigen processing and immunomodulation is poorly investigated. Here, we described how different shapes and sizes of gold nanostructures carrying adjuvant modulate carbohydrate-based antigen processing in murine dendritic cells (mDCs) and subsequent T-cell activation produce a robust antibody response. As a prototype, CpG-adjuvant-coated spherical and rod- and star-shaped AuNPs were conjugated to the tripodal Tn-glycopeptide antigen to study their DC uptake and activation of T-cells in a DCs/T-cell co-culture assay. Our results showed that the spherical and star-shaped AuNPs displayed relatively weak receptor-mediated uptake and endosomal sequestration; however, they induced a high level of T helper-1 (Th1) biasing immune responses compared with rod-shaped AuNPs. Furthermore, the in vivo administration of AuNPs showed that the small spherical and star-shaped AuNPs induced an effective anti-Tn-glycopeptide immunoglobulin (IgG) antibody response compared with rod-shaped AuNPs. These results indicated that one could obtain superior carbohydrate vaccines by varying the shape and size parameters of nanostructures.

2021-10-01·European journal of medicinal chemistry1区 · 医学

Non-carbohydrate strategies to inhibit lectin proteins with special emphasis on galectins

1区 · 医学

Review

作者: Alvala, Mallika ; Sethi, Aaftaab ; Sanam, Swetha

Lectins are a family of glycan-binding proteins, many of which have been established as key targets for therapeutic intervention. They play a central role in many physiological and cellular processes. With the advances in protein crystallography, NMR spectroscopy and computational power over the past couple of decades, the carbohydrate-receptor interactions are now well understood and characterized. Nevertheless, designing efficient carbohydrate inhibitors is a laborious endeavour. They are known to have weak affinities, unsuitable pharmacokinetic properties and highly cumbersome/complex synthetic routes. To circumvent these issues many non-carbohydrate strategies have been reported. Galectins are a sub-family of lectin proteins which have been recognized as crucial targets for a wide variety of diseases. Many candidates targeting galectins are currently in advanced stages of clinical trials. There have been a few reports of non-carbohydrate inhibitors targeting galectins which comprise of peptide-based inhibitors and a recent flourish of heterocyclic inhibitors. In this review, we have briefly highlighted the strategies like fragment-based drug-design and high-throughput screens utilized to identify non-carbohydrate based antagonists for proteins wherein the presence of a sugar was believed to be essential. Additionally, we have described the literature pertaining to non-carbohydrate inhibitors of galectins and how previous reports on rational substitution of a sugar motif could aid in design of heterocyclics that inhibit lectins/galectins. We have concluded with remarks on challenges, gap in our understanding and future perspectives concerned with rational design of non-carbohydrate molecules targeting lectins/galectins.

2020-10-01·Chemical biology & drug design4区 · 医学

Linear triazole‐linked pseudo oligogalactosides as scaffolds for galectin inhibitor development

4区 · 医学

Article

作者: Kishor, Chandan ; Grandjean, Cyrille ; Blanchard, Helen ; Lambert, Annie ; Lamoureux, Clément ; Dussouy, Christophe

Abstract:

Galectins play key roles in numerous biological processes. Their mode of action depends on their localization which can be extracellular, cytoplasmic, or nuclear and is partly mediated through interactions with β‐galactose containing glycans. Galectins have emerged as novel therapeutic targets notably for the treatment of inflammatory disorders and cancers. This has stimulated the design of carbohydrate‐based inhibitors targeting the carbohydrate recognition domains (CRDs) of the galectins. Pursuing this approach, we reasoned that linear oligogalactosides obtained by straightforward iterative click chemistry could mimic poly‐lactosamine motifs expressed at eukaryote cell surfaces which the extracellular form of galectin‐3, a prominent member of the galectin family, specifically recognizes. Affinities toward galectin‐3 consistently increased with the length of the representative oligogalactosides but without reaching that of oligo‐lactosamines. Elucidation of the X‐ray crystal structures of the galectin‐3 CRD in complex with a synthesized di‐ and tri‐galactoside confirmed that the compounds bind within the carbohydrate‐binding site. The atomic structures revealed that binding interactions mainly occur with the galactose moiety at the non‐reducing end, primarily with subsites C and D of the CRD, differing from oligo‐lactosamine which bind more consistently across the whole groove formed by the five subsites (A‐E) of the galectin‐3 CRD.

项与 PRO-GR-300 相关的新闻（医药）

2024-03-06

·GlobeNewswire-Health Care

Bioxytran Announces Preprint of Shingles Case Study Showing Clearance Using a Topical Galectin-3 Antagonist

50% Lesion clearance and regression of Herpes Zoster Neuralgia within 48 – 72 hours BOSTON, MASSACHUSETTS, March 06, 2024 (GLOBE NEWSWIRE) -- BIOXYTRAN, INC. (BIXT), (the “Company”), a clinical stage biotechnology company developing oral and intravenous drugs to treat viral diseases, announced today the preprint in ResearchGate entitled “Association of Rapid Shingles Lesion Clearance and Regression of Herpes Zoster Neuralgia in Case Study Using Topical Galectin-3 Antagonism” showed a time lapsed clearance of the shingles lesions using a topical Galectin-3 antagonist. Vaccines have been developed to prevent shingles, but there are few effective antiviral therapies capable of treating the outbreak while reducing the pain associated with the condition. The case study demonstrated a rapid response in the reduction of pain the size of the lesion area, due to a galectin antagonist. Herpes Zoster the pre-publication can be viewed at: https://www.researchgate.net/publication/378288469_Association_of_Rapid_Shingles_Lesion_Clearance_and_Regression_of_Herpes_Zoster_Neuralgia_in_Case_Study_Using_Topical_Galectin-3_Antagonism “There are preventive vaccines for shingles of variable efficacy, but the search for an efficacious therapeutic intervention, that terminates clinical progression of shingles, has so far proven elusive,” said Dr. Leslie Ajayi, Bioxytran Chief Medical Officer. “This case study constitutes a proof of concept of the benefit of using a galectin antagonist in human shingles infection. If research dollars are available, we would like to conduct an expanded clinical series, with a topical formulation of our galectin-3 antagonists in more in a varied patient pool consisting of 20 to 30 men and women. In parallel, we would like to examine the efficacy of an orally active galectin-3 antagonist compared to the topical preparation with the ultimate goal of a Randomized Controlled Trial compared against the standard of care (SOC). If our hypothesis is supported by clinical evidence, it may cause a paradigm shift and benefit, in the management of shingles and herpetic neuralgia. The subsequent possibilities are enormous, and would have an impact in the fields of virology, dermatology, and neuroscience.” About Bioxytran, Inc. Bioxytran, Inc. is a clinical stage biotechnology company pioneering a library of novel carbohydrate structures using artificial intelligence software that interprets the Nuclear Magnetic Resonance imaging of druggable targets like the galectin fold to create a rational drug design. The leading drug candidates vetted by in vitro testing, are capable of neutralizing viruses. The peer-reviewed discovery of the galectin fold located on the spike proteins of viruses such as COVID-19, RSV, and H1N1 demonstrate there exists a conserved region on the spike in which Bioxytran’s molecules achieve virus neutralization. The extent of the carbohydrate structure’s ability to neutralize untested viruses is unknown just like the initial discovery of antibiotics last century and its ability to treat a broad spectrum of bacterial infections. Applications of this platform technology extend to the treatment of significant unmet medical needs in virology, degenerative disease, and hypoxia. The leading drug candidate, Prolectin-M, is a new class of antiviral drug designed to antagonize galectins implicated in inflammatory, fibrotic, and malignant diseases. Bioxytran’s other development programs are for pulmonary fibrosis and stroke treatment. More information can be found at www.bioxytraninc.com Investor RelationsMichael Sheikh509-991-0245 mike.sheikh@bioxytraninc.com Forward-Looking Statements This press release includes forward-looking statements as defined under federal law, including those related to the performance of technology described in this press release. These forward-looking statements are generally identified by the words “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” and similar expressions, although not all forward-looking statements contain these identifying words. Such statements are subject to significant risks, assumptions and uncertainties. Known material factors that could cause Bioxytran’s actual results to differ materially from the results contemplated by such forward-looking statements are described in the forward-looking statements and risk factors in the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2021 and those risk factors set forth from time-to-time in other filings with the Securities and Exchange Commission. Bioxytran undertakes no obligation to correct or update any forward-looking statement, whether as a result of new information, future events, or otherwise, except to the extent required under federal securities laws.

疫苗临床结果临床研究

2024-02-21

·BioSpace

Bioxytran’s Oral Antiviral Drug to Enter Dose Optimization Clinical Trial for COVID-19

First Medicinal chemistry of an antiviral drug made of sugars BOSTON, MASSACHUSETTS, Feb. 21, 2024 (GLOBE NEWSWIRE) -- BIOXYTRAN, INC. (OTCQB: BIXT), (the “Company”), a clinical stage biotechnology company developing oral and intravenous drugs to treat viral diseases, announced that the first patients have been treated with ProLectin-M in its dose optimization trial. ProLectin-M is intended to become a first line treatment for standard risk COVID-19 patients, but based on the broad-spectrum in vitro discovery could easily expand to upper respiratory tract infections. Following this dose optimization trial, Bioxytran intends to use the trial data to inform the design of the Phase 3 registrational trial in India, while also adhering to the FDA’s request for additional data. The multi-center clinical trial in India will be a randomized double-blind placebo-controlled trial and is set to enroll 40 patients. ProLectin-M has previously established efficacy in two, previously conducted, peer-reviewed clinical trials with a 100% responders rate in both trials and p-values of .05 and .001. In the past decade only one other antiviral has, to our knowledge, achieved a similar preliminary efficacy profile. The Company has already established the non-toxic pro its galectin antagonists. Official additional studies are anticipated and planned in the United States. “After we complete the dose optimization trial, the next regulatory milestone is a registrational trial,” said Dr. Leslie Ajayi, Bioxytran’s medical director. “We are on the cusp of completing a clinical trial of standard risk patient that contracted COVID-19. Completing our registrational trial will position our oral galectin antagonist as the first line therapy for the single largest respiratory viral disease indication in the world. Should we achieve approval in COVID-19, we will embark on an expansion plan that will include influenza and Respiratory Syncytial Virus (RSV). We have reason to believe that our galectin antagonist is a broad spectrum antiviral capable of neutralizing a number of viruses capable of upper respiratory tract infections. We are advancing the field of Glycovirology and working toward bringing to market the potential first broad spectrum antiviral capable of neutralizing a number of viruses without changing the formulation and theoretically resistant to viral mutations.” “The discovery of a new binding region on the spike proteins of viruses has far reaching implications” said Kevin Mayo, Professor at the University of Minnesota, and also a member of Bioxytran’s scientific advisory board. “We used Nuclear Magnetic Resonance imaging to engineer / optimize a carbohydrate structure ideally suited to neutralize the spike protein of the SARS-CoV-2 virus. Before this discovery, neutralizing antibodies were only able to target the tip of the spike proteins of viruses which rapidly mutate, but after this discovery we found out that carbohydrates are able to neutralize viruses by binding to the galectin fold. The galectin fold represents a conserved structure on the spike protein virtually incapable of mutation, therefore it opens up a whole new field of research in Glycovirology. We believe a large number of viruses contain this galectin binding region on their spike proteins offering a widely druggable target that could be easily tested in a lab setting. With this discovery, we could use Nuclear Magnetic Resonance as a screening mechanism for viruses. In our COVID-19 case study we proved that the carbohydrate structures tested bound with high pico molar affinity, rarely seen with existing drugs, neutralize the viruses and that this data correlated with in vitro and the clinical trial results. We are at the dawn of a new age in virology that changes the current treatment paradigm of antivirals and vaccines to one of carbohydrate neutralization structures capable of efficiently neutralizing the virus to prevent cellular entry.” About ProLectin-M ProLectin-M is an oral galectin antagonist that prevents the entry of the SARS-CoV-2 virus into human cells. In recent clinical trials the drug achieved a 100% responders rate of negative PCR tests by day 7. In 3 days, the drug achieved an 88% responders rate of negative PCR tests. The treated population experienced no viral rebounds during the 14-day observation period. The company is preparing for a phase 3 clinical trial in order to seek regulatory approval. About Bioxytran, Inc. Bioxytran, Inc. is a clinical stage biotechnology company pioneering a library of novel carbohydrate structures using artificial intelligence software that interprets the Nuclear Magnetic Resonance spectroscopy fourier transformation mathematical process. The drug targets the galectin fold is a classical rational drug design. The leading drug candidates vetted by in vitro testing, are capable of neutralizing viruses. The peer-reviewed discovery of the galectin fold located on the spike proteins of viruses such as COVID-19, RSV, and H1N1 demonstrate there exists a conserved region on the spike in which Bioxytran’s molecules achieve virus neutralization. The extent of the carbohydrate structure’s ability to neutralize untested viruses is unknown just like the initial discovery of antibiotics last century and its ability to treat a broad spectrum of bacterial infections. Applications of this platform technology extend to the treatment of significant unmet medical needs in virology, degenerative disease, and hypoxia. The leading drug candidate, Prolectin-M, is a new class of antiviral drug designed to antagonize galectins implicated in inflammatory, fibrotic, and malignant diseases. Bioxytran’s other development programs are for pulmonary fibrosis and stroke treatment. More information can be found at Investor Relations Michael Sheikh 509-991-0245 mike.sheikh@bioxytraninc.com Forward-Looking Statements This press release includes forward-looking statements as defined under federal law, including those related to the performance of technology described in this press release. These forward-looking statements are generally identified by the words “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” and similar expressions, although not all forward-looking statements contain these identifying words. Such statements are subject to significant risks, assumptions and uncertainties. Known material factors that could cause Bioxytran’s actual results to differ materially from the results contemplated by such forward-looking statements are described in the forward-looking statements and risk factors in the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2021 and those risk factors set forth from time-to-time in other filings with the Securities and Exchange Commission. Bioxytran undertakes no obligation to correct or update any forward-looking statement, whether as a result of new information, future events, or otherwise, except to the extent required under federal securities laws.

临床3期临床结果

2023-11-08

·FierceBiotech

Durect fails alcohol-associated hepatitis trial, plans phase 3 anyway as investors scorch stock

Shares in Durect fell 62% to below $1 in premarket trading. Durect and investors have reached radically different conclusions about its severe alcohol-associated hepatitis phase 2 data. The biotech hailed “remarkable” results—on a secondary goal, in a subpopulation—but failed to persuade investors to look past the failure of the primary endpoint, causing its stock to sink. Investigators randomized around 300 patients to receive one of two doses of larsucosterol, an epigenetic modulator, or placebo. Durect had originally set out to show whether larsucosterol improved the 90-day mortality rate, before switching last year to a composite primary endpoint covering 90-day mortality and liver transplantation. Nothing good came from the change. “We had some input from some thought leaders, and we made an adjustment midstream, changed horses in the middle of a stream, which one should never do,” Durect CEO James Brown said on a conference call with investors to discuss the data. “We learnt the hard way here, unfortunately,” Brown added. “But it doesn't change … the outcome. The outcome here is we have really good mortality data.” Neither dose of larsucosterol met the primary endpoint, with the proportions of patients who were alive and transplant-free at 90 days ranging from 71.6% in the placebo group to 78.8% in the low-dose arm. Durect pinned the failure on the transplant rates and data generated outside the U.S. Narrowing the analysis to 90-day mortality at the U.S. sites, Durect linked the two larsucosterol doses to a relative risk reduction of 57% and 58% versus standard of care. The relative reduction in mortality in the entire study was 40.7% in the low-dose cohort and 34.9% in the high-dose arm, suggesting that the ex-U.S. sites, which enrolled around one-quarter of the patients, dragged on the results. “We don't know for sure exactly what happened outside the United States. It could be just random bad luck, it could be something more than that,” Brown said. “We know some characteristics are slightly different—these patients had a higher level of cirrhosis, they were older, things like that. Is it enough to make a difference? We don't know.” Durect is trying to figure out what happened while preparing to meet with the FDA in the first quarter of next year to discuss the results and the design of a planned phase 3 trial. The biotech plans to use 90-day mortality as the primary endpoint and may enroll all of the phase 3 patients in the U.S. Shares in Durect fell 62% to below $1 in premarket trading.