An Exploratory Phase I, Randomized, Observer-blind, Active-controlled, Dose-escalation Trial Evaluating the Safety, Tolerability, and Immunogenicity of an Investigational RNA-based SARS-CoV-2 Vaccine in COVID-19 Vaccine Experienced Healthy Adults

This is an exploratory Phase I, randomized, observer-blind, active-controlled, dose-escalation trial to evaluate four dose levels (DLs) of BNT162b4 given in combination with BNT162b2 Bivalent (original/Omicron BA.4/BA.5) to select a safe and tolerable dose and to evaluate BNT162b4 + BNT162b2 Bivalent (original/Omicron BA.4/BA.5) when given as Dose 1 and Dose 2 (booster) in Cohorts 1 and 2 and BNT162b4 + BNT162b2 Monovalent (OMI XBB.1.5) when given as Dose 2 (booster) in Cohorts 3a, 3b, 4a, and 4b, and 30 μg BNT162b4 when given alone as Dose 1 and Dose 2 in Cohort 5.
The trial will use a staggered dosing process schema, i.e., enrollment into the next higher dose level is done sequentially and subject to safety data from the previous dose levels, with sentinel participants in Cohorts 1, 2, 3a, and 4a. Cohort 3b investigating the same dose level as cohort 3a but in participants aged >55 years will be opened after safety data for participants aged 18-55 years in Cohort 3a has been reviewed. Enrollment into Cohorts 4a and 4b will be opened after safety data for Cohort 3a and 3b has been reviewed. Cohort 5 participants will not be randomized and will receive two doses of BNT162b4 alone after which a safety review will be performed after all participants have received Dose 2 in this cohort.
BNT162b4 plus BNT162b2 Bivalent (original/Omicron BA.4/BA.5)/Monovalent (OMI XBB.1.5) will be co-administered (as a single injection).
BNT162b4 alone will be administered as a single injection.

开始日期2022-11-08

申办/合作机构

BioNTech SE

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0 项与 SARS-CoV-2 M protein 相关的专利（医药）

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项与 SARS-CoV-2 M protein 相关的文献（医药）

2024-09-01·Journal of Biomolecular Structure and Dynamics

Exploring epigenetic drugs as potential inhibitors of SARS-CoV-2 main protease: a docking and MD simulation study.

Article

作者: Akkus, Ebru ; Kocak, Abdulkadir ; Uzuner, Ugur ; Çelik Uzuner, Selcen

The COVID-19 pandemic has caused havoc around the globe since 2019 and is considered the largest global epidemic of the twentieth century. Although the first antiviral drug, Remdesivir, was initially introduced against COVID‑19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection. FDA-approved Paxlovid (Nirmatrelvir supplemented by Ritonavir) was recently announced as a promising drug against the SARS-CoV-2 major protease (M^pro). Here we report for the first time the remarkable inhibitory potentials of lead epigenetic-targeting drugs (epi-drugs) against SARS-CoV-2 M^pro. Epi-drugs are promising compounds to be used in combination with cancer chemotherapeutics to regulate gene expression. The search for all known epi-drugs for the specific inhibition of SARS-CoV-2 M^pro was performed for the first time by consensus (three high-order program) molecular docking studies and end-state free energy calculations. Several epi-drugs were identified with highly comparable binding affinity to SARS-CoV-2 M^pro compared to Nirmatrelvir. In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 M^pro. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-M^pro complex with MM-GBSA binding free energy (ΔG_bind) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma.

2024-07-12·Organic Letters

Synthesis of Structural ADP-Ribose Analogues as Inhibitors for SARS-CoV-2 Macrodomain 1

Article

作者: Schuller, Marion ; Hoch, Nicolas C ; Rijpkema, Koen J ; Ahel, Ivan ; Balić, Pascal ; Filippov, Dmitri V ; Rieken, Sjoerd ; Wijngaarden, Sven ; Minnee, Hugo ; Codée, Jeroen D C ; Matos, Isaac A ; Todorov, Alex ; van der Veer, Miriam S ; Chang, Diego L R

Protein adenosine diphosphate (ADP)-ribosylation is crucial for a proper immune response. Accordingly, viruses have evolved ADP-ribosyl hydrolases to remove these modifications, a prominent example being the SARS-CoV-2 NSP3 macrodomain, "Mac1". Consequently, inhibitors are developed by testing large libraries of small molecule candidates, with considerable success. However, a relatively underexplored angle in design pertains to the synthesis of structural substrate mimics. Here, we present the synthesis and biophysical activity of novel adenosine diphosphate ribose (ADPr) analogues as SARS-CoV-2 NSP3 Mac1 inhibitors.

2024-07-02·Journal of Biomolecular Structure and Dynamics

In silico -based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1

Article

作者: Xie, Zhinuo ; Li, Jinyu ; Liu, Lin ; Xie, Song ; Liu, Yu-Tsen ; Zhao, Qianqian ; Wu, Juhong ; Yang, Lin ; Fu, Wei ; Cao, Shoujing

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using in silico-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1-MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (-9.8 ± 0.3 kcal/mol) and MC5 (-9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (-8.9 ± 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19.Communicated by Ramaswamy H. Sarma.

项与 SARS-CoV-2 M protein 相关的新闻（医药）

2023-01-11

·rottapharmbiotech

COVID-eVax PHASE 1 CLINICAL TRIAL RESULTS PUBLISHED

Publication January 11, 2023 Takis and Rottapharm Biotech announce the advance publication of the article “A first-in-human trial on the safety and immunogenicity of COVID-eVax, a cellular response-skewed DNA vaccine against COVID-19” by L. Aurisicchio et al in Molecular Therapy, the leading journal for research in the areas of gene transfer, vector development, stem cell manipulation, gene- and cell-based therapeutics, and vaccine development. COVID-eVax is a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. It is the first COVID-19 vaccine based on the DNA platform to reach clinical development in Europe and it was developed in synergy with an innovative technology called “electroporation”, which thanks to short electrical stimuli mediates the passage of DNA inside the cells and activates the immune system. Among the important advantages, DNA is cheap, does not need complex formulations and does not need the cold chain. The study is the result of a fruitful collaboration within a 100% Italian network: the two companies developing COVID-eVax (Takis and Rottapharm Biotech); the leader in the electroporation technology (IGEA); important academic institutions and clinical centers (San Gerardo Hospital in Monza with the University of Milan-Bicocca, the National Cancer Institute IRCCS Pascale in Naples and the Clinical Research Center in Verona); the VisMederi laboratories in Siena, worldwide expert in viral and immune assays. COVID-eVax was well tolerated and induced an immune response (binding antibodies and/or T cells) in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as Oncology. Takis Takis is a biotechnology company created by a group of scientists formerly from Merck Research Laboratories (MRL) and it is located in Rome (Italy). The group has more than 15 years of experience and proven expertise in drug discovery in Oncology and is recognized for the design and implementation of a number of innovative technologies, including that of DNA gene therapy. One of Takis’s core assets is its experience with electroporation, a technology that can be used for a variety of clinically useful applications, from vaccine development to somatic gene therapy. Takis’ pipeline includes four cancer vaccine candidates based on this technology. Takis is also actively involved in the generation of humanized monoclonal antibodies for use in oncology and infectious diseases, including COVID-19. For more information on the company, visit www.takisbiotech.it Takis contact Dr. Luigi Aurisicchio (CEO/CSO) aurisicchio@takisbiotech.it Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy) The company expertise in research and development includes medicinal / computational chemistry for small molecules, a proprietary platform for the generation and selection of new monoclonal antibodies and the development of other biological drugs and advanced therapies, the validation of new molecular targets, the pharmacological, pharmacokinetic, toxicological and pharmaceutical characterization of new drug candidates; the design and conduct of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech contact Dr. Federica Girolami (Business Development, Scientific Liaison and Drug Safety Director) federica.girolami@rottapharmbiotech.com

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