Severe Acute Respiratory syndrome 2 (SARS-CoV-2) is a respiratory virus responsible for coronavirus disease 19 (COVID-19) and the still ongoing and unprecedented global pandemic. The key viral protein for cell infection is the spike glycoprotein, a surface-exposed fusion protein that both recognizes and mediates entry into host cells. Within the spike glycoprotein, a fatty acid binding pocket (FABP) was confirmed, with the crystallization of linoleic acid (LA) occupying a well-defined site. Importantly, when the pocket is occupied by a fatty acid, an inactive conformation is stabilized, and cell recognition is hindered. In this review, we discuss ligands reported so far for this site, correlating their activity predicted through in silico studies with antispike experimental activity, assessed by either binding assays or cell-infection assays. LA was the first confirmed ligand, cocrystallized in a cryo-EM structure of the spike protein, resulting in increased stability of the inactive conformation of the spike protein. The next identified ligand, lifitegrast, was also experimentally confirmed as a ligand with antiviral activity, suggesting the potential for diverse chemical scaffolds to bind this site. Finally, SPC-14 was also confirmed as a ligand, although no inhibition assays were performed. In this review, we identified 20 studies describing small-molecule compounds predicted to bind the pocket in in silico studies and with confirmed binding or in vitro activity, either inhibitory activity against the spike-ACE2 interaction or antiviral activity in cell-based assays. When considering all ligands confirmed with in vitro assays, a good overall occupation of the pocket should be complemented with the ability to make direct interactions, both hydrophilic and hydrophobic, with key amino acid residues defining the pocket surface. Among the active compounds, long flexible carbon chains are recurrent, with retinoids capable of binding the FABP, although bulkier systems are also capable of affecting viral fitness. Compounds able to bind this site with high affinity have the potential to stabilize the inactive conformation of the SARS-CoV-2 spike protein and therefore reduce the virus's ability to infect new cells. Since this pocket is conserved in highly pathogenic human coronaviruses, including MERS-CoV and SARS-CoV, this effect could be exploited for the development of new antiviral agents, with broad-spectrum anticoronavirus activity.

2023-02-22·ACS Central Science

In Silico Discovery of Small Molecule Modulators Targeting the Achilles’ Heel of SARS-CoV-2 Spike Protein

Article

作者: Qi, Jianxun ; Zheng, Sanduo ; Li, Linjie ; Wang, Qing ; Huang, Jianhui ; Wang, Wei ; Meng, Fanhao ; Xie, Yuting ; Huang, Niu ; Ni, Xiaodan ; Meng, Yumin ; Liu, Tao

The spike protein of SARS-CoV-2 has been a promising target for developing vaccines and therapeutics due to its crucial role in the viral entry process. Previously reported cryogenic electron microscopy (cryo-EM) structures have revealed that free fatty acids (FFA) bind with SARS-CoV-2 spike protein, stabilizing its closed conformation and reducing its interaction with the host cell target in vitro. Inspired by these, we utilized a structure-based virtual screening approach against the conserved FFA-binding pocket to identify small molecule modulators of SARS-CoV-2 spike protein, which helped us identify six hits with micromolar binding affinities. Further evaluation of their commercially available and synthesized analogs enabled us to discover a series of compounds with better binding affinities and solubilities. Notably, our identified compounds exhibited similar binding affinities against the spike proteins of the prototypic SARS-CoV-2 and a currently circulating Omicron BA.4 variant. Furthermore, the cryo-EM structure of the compound SPC-14 bound spike revealed that SPC-14 could shift the conformational equilibrium of the spike protein toward the closed conformation, which is human ACE2 (hACE2) inaccessible. Our identified small molecule modulators targeting the conserved FFA-binding pocket could serve as the starting point for the future development of broad-spectrum COVID-19 intervention treatments.

项与 SPC-14 相关的新闻（医药）

2025-01-08

·GlobeNewswire-Health Care

Silo Pharma Awarded US Patent for Groundbreaking PTSD Treatment and Prepares for SPC-15 Clinical Trial

SARASOTA, FL, Jan. 08, 2025 (GLOBE NEWSWIRE) -- Silo Pharma, Inc. (Nasdaq: SILO) (“Silo” or the “Company”), a developmental stage biopharmaceutical company focused on developing novel formulations and drug delivery systems for traditional therapeutics and psychedelic treatments, today announced that the U.S. Patent and Trademark Office (USPTO) issued a Notice of Allowance for patent application 17/954,864 for “Pharmacological Prophylactics Against Stress-Induced Affective Disorders in Females.” Following receipt of the Notice of Allowance, Silo filed the final issue paperwork, paid the issue fees, and expects formal issuance of the patent in the next 90 days The patent, when formally approved, will reinforce protection for Silo’s lead asset, SPC-15, an intranasal treatment targeting post-traumatic stress disorder (PTSD). The patent includes newly added claims to U.S. Patent 11,491,120, which was issued to Silo in February 2023. “We are pleased to kick off 2025 with this expected addition to our intellectual property portfolio. The approval of this patent broadens protection for SPC-15 and expands our technology rights,” said Eric Weisblum, CEO of Silo. Silo holds an exclusive license agreement with Columbia University to further develop, manufacture, and commercialize SPC-15 globally. Through the agreement, Silo acquired extensive issued patents and pending IP patent applications for SPC-15 technology. About SPC-15 SPC-15 is a serotonin 5-HT4 receptor agonist designed to treat stress-induced disorders such as PTSD and anxiety. Delivered via an intranasal formulation, SPC-15 may qualify for the FDA’s streamlined 505(b)(2) regulatory pathway, potentially accelerating its approval process. Currently, Silo Pharma is collaborating with Columbia University on preclinical studies and holds exclusive rights to develop and commercialize SPC-15 globally. About Silo Pharma Silo Pharma Inc. (Nasdaq: SILO) is a developmental stage biopharmaceutical company developing novel therapeutics that address underserved conditions including stress-induced psychiatric disorders, chronic pain conditions, and central nervous system (CNS) diseases. Silo focuses on developing traditional therapies and psychedelic treatments in novel formulations and drug delivery systems. The Company’s lead program, SPC-15, is an intranasal treatment targeting PTSD and stress-induced anxiety disorders. SP-26 is a time-release ketamine-loaded implant for fibromyalgia and chronic pain relief. Silo’s two preclinical programs are SPC-14, an intranasal compound for the treatment of Alzheimer’s disease, and SPU-16, a CNS-homing peptide targeting multiple sclerosis (MS). Silo’s research and development programs are conducted through collaborations with universities and independent laboratories. For more information, visit www.silopharma.com and connect on social media at LinkedIn , X , and Facebook . Forward-Looking Statements This news release contains "forward-looking statements" within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. These statements are identified using words “could”, “believe”, “anticipate”, “intend”, “estimate”, “expect”, “may”, “continue”, “predict”, “potential”, and similar expressions that are intended to identify forward-looking statements. Such statements involve known and unknown risks, uncertainties, and other factors that could cause the actual results of Silo Pharma, Inc. (“Silo” or “the Company”) to differ materially from the results expressed or implied by such statements, including changes to anticipated sources of revenues, future economic and competitive conditions, difficulties in developing the Company’s technology platforms, retaining and expanding the Company’s customer base, fluctuations in consumer spending on the Company’s products and other factors. Accordingly, although the Company believes that the expectations reflected in such forward-looking statements are reasonable, there can be no assurance that such expectations will prove to be correct. The Company disclaims any obligations to publicly update or release any revisions to the forward-looking information contained in this press release, whether as a result of new information, future events, or otherwise, after the date of this press release or to reflect the occurrence of unanticipated events except as required by law. Contact 800-705-0120 investors@silopharma.com

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2024-12-18

·GlobeNewswire-Health Care

Silo Pharma Initiates Pharmacokinetic and Tolerability Study for SP-26 Targeting Chronic Pain and Fibromyalgia

Key preclinical milestone for novel, non-opioid extended-release pain therapeutic SARASOTA, FL, Dec. 18, 2024 (GLOBE NEWSWIRE) -- Silo Pharma, Inc. (Nasdaq: SILO) (“Silo” or the “Company”), a developmental stage biopharmaceutical company focused on developing novel formulations and drug delivery systems for traditional therapeutics and psychedelic treatments, today announced the initiation of a pharmacokinetic (PK) and tolerability study in partnership with its contract research organization (CRO), AmplifyBio. The study is designed to assess the pharmacokinetics of Silo’s dissolvable ketamine-based injectable implant, SP-26, in a minipig model. SP-26 is being developed as a self-administered, non-opioid therapeutic aimed at treating chronic pain and fibromyalgia. The non-GLP study, set to span three weeks, will investigate the absorption, distribution, metabolism, and excretion (ADME) of extended-release ketamine hydrochloride implants. Two distinct polymer formulations will be tested at varying dose levels. “So far this year we have conducted several studies of our SP-26 ketamine implants including analytical testing and small batch proof-of-concept extrusion trials, manufacturing and production evaluation, and sterilization and dissolution tests, with what we believe are encouraging results,” said Silo CEO Eric Weisblum. “The advancement of this program into animal studies is an important milestone achievement as we work to bring a safe and effective and to our knowledge, first-of-its-kind ketamine treatment for those living with chronic pain.” “AmplifyBio is honored to support Silo Pharma in this critical safety milestone for SP-26. We understand and take seriously the trust put in us to execute the PK study efficiently and with excellence,” said Jerry Hacker, EVP, and Chief Commercial Officer for AmplifyBio. About SP-26 SP-26 is a ketamine-based injectable dissolvable polymer implant for the treatment of chronic pain and fibromyalgia. The subcutaneous implant is being designed to safely regulate dosage and time release of the pain-relieving treatment. If clinically successful, SP-26 could qualify for the FDA’s streamlined 505(b)(2) regulatory pathway for drug approval. About Silo Pharma Silo Pharma Inc. (Nasdaq: SILO) is a developmental stage biopharmaceutical company developing novel therapeutics that address underserved conditions including stress-induced psychiatric disorders, chronic pain conditions, and central nervous system (CNS) diseases. Silo focuses on developing traditional therapies and psychedelic treatments in novel formulations and drug delivery systems. The Company’s lead program, SPC-15, is an intranasal treatment targeting PTSD and stress-induced anxiety disorders. SP-26 is a time-release ketamine-loaded implant for fibromyalgia and chronic pain relief. Silo’s two preclinical programs are SPC-14, an intranasal compound for the treatment of Alzheimer’s disease, and SPU-16, a CNS-homing peptide targeting multiple sclerosis (MS). Silo’s research and development programs are conducted through collaborations with universities and independent laboratories. For more information, visit www.silopharma.com and connect on social media at LinkedIn , X , and Facebook . Forward-Looking Statements This news release contains "forward-looking statements" within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. These statements are identified by the use of words “could”, “believe”, “anticipate”, “intend”, “estimate”, “expect”, “may”, “continue”, “predict”, “potential”, and similar expressions that are intended to identify forward-looking statements. Such statements involve known and unknown risks, uncertainties, and other factors that could cause the actual results of Silo Pharma, Inc. (“Silo” or “the Company”) to differ materially from the results expressed or implied by such statements, including changes to anticipated sources of revenues, future economic and competitive conditions, difficulties in developing the Company’s technology platforms, retaining and expanding the Company’s customer base, fluctuations in consumer spending on the Company’s products and other factors. Accordingly, although the Company believes that the expectations reflected in such forward-looking statements are reasonable, there can be no assurance that such expectations will prove to be correct. The Company disclaims any obligations to publicly update or release any revisions to the forward-looking information contained in this news release, whether as a result of new information, future events, or otherwise, after the date of this news release or to reflect the occurrence of unanticipated events except as required by law. Contact 800-705-0120 investors@silopharma.com

临床研究

2024-11-29

·GlobeNewswire-Health Care

Silo Pharma Enters Joint Development Agreement for SP-26 Ketamine Implant Device Targeting Pain Management

Prototype development and feasibility testing underway for optimized subcutaneous delivery SARASOTA, FL, Nov. 29, 2024 (GLOBE NEWSWIRE) -- Silo Pharma, Inc. (Nasdaq: SILO) (“Silo” or the “Company”), a developmental stage biopharmaceutical company focused on developing novel formulations and drug delivery systems for traditional therapeutics and psychedelic treatments, today announced a collaboration agreement with Kymanox for specialized design and development of a subcutaneous insertion device for SP-26, the Company’s ketamine-loaded implant therapeutic targeting fibromyalgia and chronic pain. Under terms of the agreement, Kymanox will conduct an initial proof-of-concept design phase followed by full system prototype and feasibility testing to determine optimal insertion depth in tissue. “Previous analytical testing and proof-of-concept extrusion trials have confirmed the optimal formulation for our SP-26 implants. Now we are advancing this program to develop a novel insertion device that is intended to be tested in continuing preclinical studies,” said Silo CEO Eric Weisblum. “We are pleased with the steady progress we are making with our proposed ketamine implants, which are being uniquely designed with a goal of providing sustained relief of chronic pain.” Preclinical research to date has focused, in part, on ensuring that the safety profile of SP-26 aligns with FDA requirements for potential at-home therapeutic designation. If approved, SP-26 could become the first at-home injectable ketamine-based therapeutic. In addition to the SP-26 agreement, Kymanox is Silo’s regulatory partner for SPC-15, a targeted prophylactic treatment for stress-induced affective disorders including PTSD. About SP-26 Silo’s SP-26 is a ketamine-based injectable dissolvable polymer implant for the treatment of chronic pain and fibromyalgia. The subcutaneous implant is being designed to safely regulate dosage and time release of the pain-relieving treatment. If clinically successful, SP-26 could qualify for the FDA’s streamlined 505(b)(2) regulatory pathway for drug approval. About Silo Pharma Silo Pharma Inc. (Nasdaq: SILO) is a developmental stage biopharmaceutical company developing novel therapeutics that address underserved conditions including stress-induced psychiatric disorders, chronic pain conditions, and central nervous system (CNS) diseases. Silo focuses on developing traditional therapies and psychedelic treatments in novel formulations and drug delivery systems. The Company’s lead program, SPC-15, is an intranasal treatment targeting PTSD and stress-induced anxiety disorders. SP-26 is a time-release ketamine-loaded implant for fibromyalgia and chronic pain relief. Silo’s two preclinical programs are SPC-14, an intranasal compound for the treatment of Alzheimer’s disease, and SPU-16, a CNS-homing peptide targeting multiple sclerosis (MS). Silo’s research and development programs are conducted through collaborations with universities and independent laboratories. For more information, visit www.silopharma.com and connect on social media at LinkedIn, X, and Facebook. Forward-Looking Statements This news release contains "forward-looking statements" within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. These statements are identified by the use of words “could”, “believe”, “anticipate”, “intend”, “estimate”, “expect”, “may”, “continue”, “predict”, “potential”, and similar expressions that are intended to identify forward-looking statements. Such statements involve known and unknown risks, uncertainties, and other factors that could cause the actual results of Silo Pharma, Inc. (“Silo” or “the Company”) to differ materially from the results expressed or implied by such statements, including changes to anticipated sources of revenues, future economic and competitive conditions, difficulties in developing the Company’s technology platforms, retaining and expanding the Company’s customer base, fluctuations in consumer spending on the Company’s products and other factors. Accordingly, although the Company believes that the expectations reflected in such forward-looking statements are reasonable, there can be no assurance that such expectations will prove to be correct. The Company disclaims any obligations to publicly update or release any revisions to the forward-looking information contained in this presentation, whether as a result of new information, future events, or otherwise, after the date of this presentation or to reflect the occurrence of unanticipated events except as required by law. Contact 800-705-0120 investors@silopharma.com

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100 项与 SPC-14 相关的药物交易

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