CB‐0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti‐HIV candidate: Computational and in vitro approach

Article

作者: Kumar, Ashish

Abstract:

The CC chemokine receptor 5 (CCR5) serves a pivotal role in human immunodeficiency virus 1 (HIV‐1) infection by acting as a co‐receptor and facilitating the binding of the viral envelope glycoprotein (env). Maraviroc (MVC), a Food and Drug Administration‐approved monocarboxylic acid amide, is one of the CCR5 inhibitors employed in HIV treatment. Despite the existence of approved drugs, the emergence of drug resistance underscores the necessity for novel compounds to combat resistance and enhance therapeutic efficacy. In this study, CB‐0821, identified from the ChemBridge library, emerged as a promising CCR5 inhibitor. Molecular dynamics simulations indicate comparable dynamic properties for CB‐0821 and MVC. In silico comparisons with other CCR5 inhibitors emphasize CB‐0821's superior binding affinity, positioning it as a potential lead compound. Evaluations of the dissociation constant (Ki) and absorption, distribution, metabolism, and excretion predictions suggest CB‐0821 as a well‐tolerated drug. Furthermore, the dose‐dependent inhibition of CCR5 by CB‐0821 in Peripheral blood mononuclear cells (PBMCs) (ranging from 10 to 200 nM) demonstrates efficacy, coupled with nontoxicity to Vero cells at concentrations up to 500 nM. These results underscore the potential of CB‐0821 in HIV antiviral therapy, calling for additional preclinical validations before advancing to clinical considerations.

2024-07-25·JOURNAL OF PHYSICAL CHEMISTRY B

Hybrid Virtual Screening Approach to Predict Novel Natural Compounds against HIV-1 CCR5

Article

作者: Eid, Abdulrahman M ; Khaled, Mohamed ; Elfiky, Abdo A ; Selim, Abdallah

BACKGROUND:

Human immunodeficiency virus (HIV) infection continues to pose a major global health challenge. HIV entry into host cells via membrane fusion mediated by the viral envelope glycoprotein gp120/gp41 is a key step in the HIV life cycle. CCR5, expressed on CD4+ T cells and macrophages, acts as a coreceptor facilitating HIV-1 entry. The CCR5 antagonist maraviroc is used to treat HIV infection. However, it can cause adverse effects and has limitations such as only inhibiting CCR5-tropic viruses. There remains a need to develop alternative CCR5 inhibitors with improved safety profiles.

PROBLEM STATEMENT:

Natural products may offer advantages over synthetic inhibitors including higher bioavailability, binding affinity, effectiveness, lower toxicity, and molecular diversity. However, screening the vast chemical space of natural compounds to identify novel CCR5 inhibitors presents challenges. This study aimed to address this gap through a hybrid ligand-based pharmacophore modeling and molecular docking approach to virtually screen large natural product databases.

METHODS:

A reliable pharmacophore model was developed based on 311 known CCR5 antagonists and validated against an external data set. Five natural product databases containing over 306,000 compounds were filtered based on drug-likeness rules. The validated pharmacophore model screened the databases to identify 611 hits. Key residues of the CCR5 receptor crystal structure were identified for docking. The top hits were docked, and interactions were analyzed. Molecular dynamics simulations were conducted to examine complex stability. Computational prediction evaluated pharmacokinetic properties.

RESULTS:

Three compounds exhibited similar interactions and binding energies to maraviroc. MD simulations demonstrated complex stability comparable to maraviroc. One compound showed optimal predicted absorption, minimal metabolism, and a lower likelihood of interactions than maraviroc.

CONCLUSION:

This computational screening workflow identified three natural compounds with promising CCR5 inhibition and favorable pharmacokinetic profiles. One compound emerged as a lead based on bioavailability potential and minimal interaction risk. These findings present opportunities for developing alternative CCR5 antagonists and warrant further experimental investigation. Overall, the hybrid virtual screening approach proved effective for mining large natural product spaces to discover novel molecular entities with drug-like properties.

2024-05-01·iScience

Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis

Article

作者: Wang, Qiong ; Xie, Zhao-Xiang ; Li, Kai-Wen ; Gao, Ze ; Xie, Jun-Jia ; Zhuang, Rui-Lin ; Peng, Shi-Rong ; Huang, Hai ; Li, Bing-Heng ; Xiong, Zhi ; Yu, Shun-Li

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

项与 CCR5 antagonists (Tali Digital Ltd) 相关的新闻（医药）

2023-07-11

·BioSpace

CytoDyn Announces Company Updates and Investment Community Update Webcast

Claim Filed in Former CRO Litigation for Damages Exceeding $100M Dr. Arman Returns from Medical Leave as SVP of Business Operations Webcast to be held Monday, July 24th, 2023, at 1 PM PT / 4 PM ET VANCOUVER, Washington, July 11, 2023 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTCQB: CYDY) (“CytoDyn” or the “Company”), a clinical-stage biotechnology company developing leronlimab, a CCR5 antagonist with the potential for multiple therapeutic indications, today announced that it has filed a supplemental Statement of Claim and formally requested a hearing date in its litigation proceeding against Amarex Clinical Research LLC (“Amarex”), the Company’s former Contract Research Organization (“CRO”). The Company also announced that Dr. Cyrus Arman has returned to the Company, following his medical leave of absence, as Senior Vice President of Business Operations, a new role in which he will be working reduced hours. A search has begun for a new President and/or Chief Executive Officer, while Antonio Migliarese, the Company’s Chief Financial Officer, will continue to serve as interim President. Amarex provided clinical trial management and regulatory services to CytoDyn from 2013 to 2021. The Company took preliminary legal action against Amarex in late 2021, and has now filed a supplemental Statement of Claim and requested a final hearing date be set in the arbitration matter pending with the American Arbitration Association. Should the Company prevail at the final hearing, the Company will be entitled to recover its damages and legal fees incurred from Amarex. The Company’s Statement of Claim, among other things, alleges that Amarex failed to perform its obligations and services under the master services agreement and work orders that governed the relationship between the parties, including failure to perform services to an acceptable professional standard and billing the Company for services it did not perform. Due to Amarex’s failures, the Company suffered substantial damages and will be seeking an award in excess of $100 million at the final hearing. Antonio Migliarese, CytoDyn’s interim President, commented, “The recent filing against Amarex is the next step towards holding Amarex accountable for the damages they inflicted on the Company which we will aggressively continue to pursue. This filing builds on the momentum obtained from the previous favorable ruling by the U.S. District Court for the District of Maryland in our dispute with Amarex. We are very confident in our claims, in particular, due to the results of independent and FDA audits that have been conducted as to Amarex’s services, and regulatory action taken by the FDA against Amarex. Our attorneys will be taking all steps necessary to maximize recovery from Amarex.” Dr. Arman, SVP of Business Operations, said, “I am excited to feel well enough to return from medical leave and contribute to CytoDyn. This new role will allow me to support CytoDyn and the development of leronlimab, which I continue to believe in and am very confident and optimistic about the potential of, while continuing to tend to my health.” Tanya Urbach, Board Chair, also stated, “We are happy Dr. Arman is able to return, albeit not in his previous capacity, and lend his demonstrated knowledge and talent to the Company. With this group’s cumulative regulatory, clinical, and industry expertise, it is my belief that we currently have the strongest leadership team of board members, executives, and advisors since I began my tenure as Chair. Although the Board has commenced a search for a President and/or CEO, the current team is beyond well-equipped.” Webcast Information The Company will host the following live webcast to provide a Company update: Date: Monday, July 24, 2023 Time: 1:00 PM PT / 4:00 PM ET Access: Questions: Please submit any questions prior to the webcast, and not later than Noon PT, Thursday, July 20, 2023. Questions can be submitted via email to: ir@cytodyn.com. Per CytoDyn’s current policy, the presenters will not be able to take live questions during the webcast. This is a livestream presentation. Participants are encouraged to login early prior to the start of the event. The replay will be available approximately 60 minutes after the conclusion of the webcast and can be accessed via the above link until August 24, 2023. About CytoDyn CytoDyn is a clinical-stage biotechnology company focused on the development and commercialization of leronlimab, an investigational humanized IgG4 monoclonal antibody (mAb) that is designed to bind to C-C chemokine receptor type 5 (CCR5), a protein on the surface of certain immune system cells that is believed to play a role in numerous disease processes. CytoDyn is studying leronlimab in multiple therapeutic areas, including infectious disease, cancer, and autoimmune conditions. Forward-Looking Statements This press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements may include statements about leronlimab, its ability to provide positive health outcomes, the Company’s ability to resolve the clinical hold imposed by the U.S. Food and Drug Administration (the “FDA”), the Company's ability to implement a successful operating strategy for the development of leronlimab and thereby create shareholder value, the ability to obtain regulatory approval of the Company’s drug products for commercial sales, and the market for actual commercial sales, the recovery of damages in the Amarex dispute, and the strength of the Company’s leadership team. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties, including: (i) the regulatory determinations of leronlimab’s safety and effectiveness to treat the diseases and conditions for which we are studying the product by the FDA and various drug regulatory agencies in other countries; (ii) the Company’s ability to raise additional capital to fund its operations; (iii) the Company’s ability to meet its debt and other payment obligations; (iv) the Company’s ability to recruit and retain key employees; (v) the Company’s ability to enter into partnership or licensing arrangements with third parties; (vi) the timely and sufficient development, through internal resources or third-party consultants, of analyses of the data generated from the Company’s clinical trials required by the FDA or other regulatory agencies in connection with applications for approval of the Company’s drug product; (vii) the Company’s ability to achieve approval of a marketable product; (viii) the design, implementation and conduct of the Company’s clinical trials; (ix) the results of any such clinical trials, including the possibility of unfavorable clinical trial results; (x) the market for, and marketability of, any product that is approved; (xi) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company’s products; (xii) regulatory initiatives, compliance with governmental regulations and the regulatory approval process; (xiii) legal proceedings, investigations or inquiries affecting the Company or its products; (xiv) general economic and business conditions; (xv) changes in foreign, political, and social conditions; (xvi) stockholder actions or proposals with regard to the Company, its management, or its board of directors; and (xvii) various other matters, many of which are beyond the Company’s control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and risk factors or cautionary statements included in subsequent Form 10-Qs and Form 8-Ks, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release. CONTACT Investor Relations CytoDyn Inc. Office: 360.980.8524 ir@cytodyn.com

高管变更

2023-07-06

·PipelineReview

Complement C5 Inhibitors & C5 Receptor Antagonists: a Competitor Analysis

BARCELONA, Spain I July 6, 2023 I La Merie Publishing released its newest product reviewing the pipeline of complement C5 inhibitors and C5 receptor antagonists: Competitor Analysis: Complement C5 Inhibitors & C5 Receptor Antagonists This Competitive Intelligence report about Complement C5 Inhibitors & C5 Receptor Antagonists provides a competitor evaluation in the field of mainly recombinant antibodies, but also proteins, peptides, RNA and small molecules acting as inibitors of complement C5 or antagonists of the C5 receptor as of July 2023. With annual sales of more than US$ 5.7 bln in 2022, first and second generation C5 inhibitor antibodies Soliris and Ultomiris from AstraZeneca (acquired Alexion Pharmaceuticals) have set the stage for next generation biosuperiors as well as biosimilars of a commercially successful and clinically effective treatment of complement C5 mediated diseases. New treatment modalities in development aim at improving the mode and frequency of administration as well as the scope of indications. Players in the field not only include small and medium biotech, but also Big Pharmas This product consists of a competitor description in a tabular format provided as a pdf document and an one-month online access to La Merie Publishing’s online database for this product (report code: LMCA0012) (prerequisite: access to internet). Both deliverables (pdf and database credentials) are sent by e-mail within one day, usually within one hour. The pdf report includes a compilation of currently active projects in research and development of inhibitors of complement C5 or antagonists of the C5a receptor. In addition, the pdf report lists company-specific R&D pipelines of C5 inhibitors & C5R antagonists. Competitor projects are listed in a tabular format providing information on: About Competitor Analysis reports: Competitor Analysis reports deliver NO-FRILLS, but concise information about the pipeline of R&D projects for targets, diseases, technologies and companies at low prices. The information is provided in a tabular format and fully referenced. The LMCA0012 report database provides access to the history of each project with links to the source of information (press release, homepage, abstracts, presentations, annual reports etc). Furthermore, the database allows export of data into a Word or Excel document. The report “ Competitor Analysis: Complement C5 Inhibitors & C5 Receptor Antagonists ” can be acquired at La Merie Publishing’s online store: https://lamerie.com/report/competitor-analysis-complement-c5-inhibitors-c5-receptor-antagonists/ About La Merie Publishing La Merie Publishing is an independent business information provider for the biotechnology and pharmaceutical industry. La Merie Publishing prepares brief and full reports. La Merie Publishing products can be purchased in the online store www.lamerie.com and from selected Resellers. La Merie Publishing offers the service of custom report preparation for corporate clients, including, but not limited to, pipeline analysis reports, drug profiles and any other competitive intelligence elaboration of interest. SOURCE: La Merie Publishing

2023-05-24

·GlobeNewswire-Health Care

CytoDyn Announces President Takes Medical Leave of Absence

Antonio Migliarese assumes interim President roleDr. Melissa Palmer appointed interim Chief Medical OfficerDr. Salah Kivlighn joins CytoDyn as clinical and strategic advisor VANCOUVER, Washington, May 24, 2023 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTCQB: CYDY) ("CytoDyn" or the "Company"), a biotechnology company developing leronlimab, a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that Dr. Cyrus Arman, the Company’s President, has taken a medical leave of absence. During Dr. Arman’s absence, Antonio Migliarese, the Company’s Chief Financial Officer, will assume interim President responsibilities. Mr. Migliarese will be supported by the Company’s recently appointed interim Chief Medical Officer, Dr. Melissa Palmer, as well as Dr. Salah Kivlighn, who recently joined the Company as a clinical and strategic advisor, in collectively leading the Company’s continued priorities of lifting the clinical hold on the use of leronlimab in the HIV population, advancing the development of the NASH phase 2b clinical trial for submission to the FDA, and exploring potential strategic business opportunities. The Company plans to host an investment community webcast on a to-be-announced date in the near future. Dr. Palmer is an experienced industry executive and internationally renowned Hepatologist. She has held leadership positions at various biotech and pharmaceutical companies, including CMO of Gannex/Ascletis and Head of Liver Disease Clinical Development at Takeda Pharmaceutical Company. At both Shire plc (acquired by Takeda in 2019) and Kadmon Corporation (acquired by Sanofi Company in 2021), Dr. Palmer led the global development of NASH and other liver disease programs. She was previously a clinical professor at NYU Langone Medical Center and the director of Hepatology at NYU Plainview, NY. Earlier in her career, Dr. Palmer maintained a solo medical practice devoted to treating patients with liver disease for 20 years. Since 1991, Dr. Palmer has served as a hepatology consultant to more than 60 biotech and pharmaceutical companies and has been a primary investigator for numerous clinical trials in NASH and other liver diseases. Dr. Palmer has authored over 100 publications, abstracts, manuscripts, and book chapters, in addition to the best-selling book "Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease." Dr. Palmer, either as the primary author or co-author with colleagues from the FDA, has published several guidelines concerning drug-induced liver injury among patients in clinical trials evaluating potential drugs to treat NASH and other liver diseases. She trained in Hepatology at Mount Sinai School of Medicine, where she also received her M.D. degree. She received her Bachelor of Science degree from Columbia University in New York City. Dr. Kivlighn, who is currently President and Managing Member of The Kivlighn Group, LLC, a company that provides strategic consulting services to companies across the biotech and pharmaceutical industry, brings to the Company more than 30 years of industry experience. Having held both scientific and commercial leadership roles, Dr. Kivlighn is a rare blend of science and business acumen. Recently, Dr. Kivlighn served as CEO of HepaTx Corporation, providing strategic, financial, and operational leadership. Prior to HepaTx, Dr. Kivlighn served as the Senior Vice President of Global Strategic Marketing and Program Operations for United States Pharmacopeia (“USP”), the official pharmacopeia for the United States. At USP, he created a new division with members in China, India, Europe, Latin America, and APAC, delivering a revitalized sales and marketing culture that yielded an average compound annual growth rate of 8.6%. Before his tenure at USP, he served as Commercial Vice President of Kite Pharma, Inc., now a subsidiary of Gilead Sciences. As Global Product Development Team Lead at MedImmune, Inc., a subsidiary of AstraZeneca, Dr. Kivlighn and his team spearheaded the development of a Leukemia drug, LUMOXITI® (moxetumomab pasudotox) which was acquired by INNATE Pharma, an independent clinical-stage biotech company. He also serves in advisory and board member roles for several companies. Dr. Kivlighn began his career at Merck & Co. (“Merck”) where he held positions of increasing responsibility during his 15-year tenure. While at Merck, Dr. Kivlighn was the lead scientist for the discovery and development of Cozaar® (losartan), and later helped to lead the massive growth of Cozaar® to $3.5B in worldwide revenue. As a scientist and marketer, Dr. Kivlighn contributed to the successful launch of a number of trials. At Merck, he also co-led the development and commercialization of RotaTeq® leading to an $800M franchise; RotaTeq® was awarded universal recommendation by the Advisory Committee on Immunization Practices. Among Dr. Kivlighn’s many accolades, his team earned the prestigious Prix Galien Award for Best Biotechnology Product for RotaTeq®. In addition, he earned the AstraZeneca CEO Award for his leadership during the development of LUMOXITI® (moxetumomab pasudotox). Dr. Kivlighn is a sought-after global speaker and thought leader and has authored more than 77 peer-reviewed scientific publications. He holds a Ph.D. in Pharmacology from Texas Medical Center (University of Houston, Baylor College of Medicine & University of Texas Medical School), completing a fellowship in Integrated Physiology under the esteemed advisors Arthur C. Guyton and Thomas Lohmeier at the University of Mississippi Medical Center, and a Bachelor of Science in Distributed Studies from Iowa State University. Dr. Palmer said, "I am excited about joining CytoDyn to support the further development of leronlimab following its impressive phase 2 data in patients with NASH. I am eager to help accelerate the NASH clinical development program and look forward to working with the Company's talented team and Dr. Kivlighn, with whom I’ve had the pleasure of working in the past.” Dr. Kivlighn stated, “I have had the pleasure of getting to know the Company’s Board of Directors and Tanya, Cyrus and Antonio, in addition to gaining an understanding of leronlimab, the current status of its development programs, the potential it has in various indications, and the current objectives related to the HIV clinical hold and future NASH clinical trial. I am thrilled to be able to leverage my experience and knowledge of the Company to support Antonio and the Company’s clinical, regulatory, and strategic efforts during Dr. Arman’s leave of absence.” Tanya Urbach, Board Chair, said “Given the unanticipated circumstances, we are blessed to have had such a talented CMO as Dr. Palmer recently join the Company. We are further grateful for Dr. Kivlighn’s willingness to step in and support Antonio and the team at this time. Dr. Palmer and Dr. Kivlighn each bring significant experience not only in the oncology and NASH spaces but also in leadership roles with clinical and drug development companies. I believe these two individuals, coupled with Antonio’s strong management abilities, will allow us to not miss a beat during Cyrus’s absence.” About CytoDyn CytoDyn is a clinical-stage biotechnology company focused on the development and commercialization of leronlimab, an investigational humanized IgG4 monoclonal antibody (mAb) that is designed to bind to C-C chemokine receptor type 5 (CCR5), a protein on the surface of certain immune system cells that is believed to play a role in numerous disease processes. CytoDyn is studying leronlimab in multiple therapeutic areas, including infectious disease, cancer, and autoimmune conditions. Forward-Looking Statements This press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements may include statements about leronlimab, its ability to provide positive health outcomes, the Company’s ability to resolve the clinical hold imposed by the FDA, the Company's ability to develop a successful operating strategy and thereby create shareholder value, the ability to obtain regulatory approval of the Company’s drug products for commercial sales, and the market for actual commercial sales. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties, including: (i) the regulatory determinations of leronlimab’s safety and effectiveness to treat the diseases and conditions for which we are studying the product by the U.S. Food and Drug Administration (“FDA”) and various drug regulatory agencies in other countries; (ii) the Company’s ability to raise additional capital to fund its operations; (iii) the Company’s ability to meet its debt and other payment obligations; (iv) the Company’s ability to recruit and retain key employees; (v) the Company’s ability to enter into partnership or licensing arrangements with third parties; ((vi) the timely and sufficient development, through internal resources or third-party consultants, of analyses of the data generated from the Company’s clinical trials required by the FDA or other regulatory agencies in connection with applications for approval of the Company’s drug product; (vii) the Company’s ability to achieve approval of a marketable product; (viii) the design, implementation and conduct of the Company’s clinical trials; (ix) the results of any such clinical trials, including the possibility of unfavorable clinical trial results; (x) the market for, and marketability of, any product that is approved; (xi) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company’s products; (xii) regulatory initiatives, compliance with governmental regulations and the regulatory approval process; (xiii) legal proceedings, investigations or inquiries affecting the Company or its products; (xiv) general economic and business conditions; (xv) changes in foreign, political, and social conditions; (xvi) stockholder actions or proposals with regard to the Company, its management, or its board of directors; and (xvii) various other matters, many of which are beyond the Company’s control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and risk factors or cautionary statements included in subsequent Form 10-Qs and Form 8-Ks, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release. CONTACT Investor RelationsCytoDyn Inc.Office: 360.980.8524ir@cytodyn.com

高管变更临床2期并购

100 项与 CCR5 antagonists (Tali Digital Ltd) 相关的药物交易

登录后查看更多信息