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KR-102962154-B1 - Method for optimizing broad-spectrum anti-coronavirus lipopeptides as viral membrane fusion inhibitors and uses thereof

KR102962154B1KR 102962154 B1KR102962154 B1KR 102962154B1KR-102962154-B1

Abstract

A broad-spectrum anti-SARS-CoV-2 lipopeptide, a method for preparing the same, a viral membrane fusion inhibitor comprising the lipopeptide, and the use of the lipopeptide in the preparation of a pharmaceutical composition for the prevention and treatment of a disease caused by a coronavirus are provided. The structure of the lipopeptide is represented by the following formula I or formula II, wherein X1 is an amino-terminal protecting group; X2 is a polypeptide having the amino acid sequence of (EAAAK)n or A[(EAAAK)n]A, where n is a natural number of 5 or less representing the number of repetitions of the EAAAK sequence; X3 is lysine or cysteine or 2,3-diaminopropionic acid or ornithine or 2,4-diaminobutyric acid or 2,7-diaminoheptonic acid; X4 is a lipophilic compound group; and X5 is a carboxyl-terminal protecting group. Chemical Formula I ; Chemical Formula II

Inventors

  • 허 위시옌
  • 주 위옌메이
  • 총 후이후이
  • 리우 니옌

Assignees

  • 유케어 파마슈티컬 그룹 컴퍼니 리미티드

Dates

Publication Date
20260511
Application Date
20220519
Priority Date
20220221

Claims (10)

  1. A compound of the following chemical formula I, or a pharmaceutically acceptable salt thereof: Chemical Formula I In chemical formula I, X1 is Ac and; In chemical formula I, X₂ is a polypeptide having the amino acid sequence of EAAAK; In chemical formula I, X₃ is lysine; In chemical formula I, X₄ is a lipophilic compound group modified from X₃ , and said lipophilic compound is cholesteryl hemisuccinate; In chemical formula I, X₅ is NH₂ .
  2. Polymers such as (a1) or (a2) as follows: (a1) A polymer formed by the compound according to claim 1; (a2) A polymer formed from a pharmaceutically acceptable salt according to paragraph 1.
  3. In paragraph 1, A compound or its pharmaceutically acceptable salt that is (b1) or (b2) as follows: (b1) A compound or its pharmaceutically acceptable salt for use as a coronavirus membrane fusion inhibitor; (b2) A compound or its pharmaceutically acceptable salt for use in the prevention and/or treatment of diseases caused by coronavirus.
  4. A product comprising a compound according to paragraph 1 or a pharmaceutically acceptable salt thereof, A product having a use including using the product as a coronavirus membrane fusion inhibitor for the purpose of preventing and/or treating diseases caused by coronavirus.
  5. A method for improving the antiviral activity and / or stability of a viral membrane fusion inhibitor in treating a disease caused by a coronavirus in mammals other than humans, comprising the step of obtaining a lipopeptide by linking a linker polypeptide X2 as a linking arm to a viral membrane fusion inhibitor X3 ( X4 ) group before modification, wherein the lipopeptide is a compound of the following chemical formula I: Chemical Formula I In chemical formula I, X1 is Ac and; In chemical formula I, linker polypeptide X2 has the amino acid sequence of EAAAK; In the X₃ ( X₄ ) group in Chemical Formula I, X₄ is modified from the X₃ phase; X₃ is lysine; X₄ is a lipophilic compound group, and the lipophilic compound is cholesteryl hemisuccinate; In chemical formula I, X₅ is NH₂ .
  6. A method for preparing a modified viral membrane fusion inhibitor, comprising the step of obtaining a lipopeptide by linking a pre-modification viral membrane fusion inhibitor with an X3 ( X4 ) group using a linker polypeptide X2 having the amino acid sequence of EAAAK as a linking arm, wherein the lipopeptide is the modified viral membrane fusion inhibitor and is a compound of the following chemical formula I: Chemical Formula I In chemical formula I, X1 is Ac and; In the X₃ ( X₄ ) group in Chemical Formula I, X₄ is modified from the X₃ phase; X₃ is lysine; X₄ is a lipophilic compound group, and the lipophilic compound is cholesteryl hemisuccinate; In chemical formula I, X₅ is NH₂ .
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Description

Method for optimizing broad-spectrum anti-coronavirus lipopeptides as viral membrane fusion inhibitors and uses thereof The present disclosure relates to a method for optimizing a broad-spectrum anti-coronavirus lipopeptide that is a viral membrane fusion inhibitor and the use thereof. Membrane fusion is a very important biological phenomenon, and physiological processes such as the formation of fertilized eggs and intracellular endoplasmic reticulum transport are achieved through membrane fusion. Many viruses that seriously harm human health, such as human immunodeficiency virus (HIV), influenza virus, hepatitis virus, Ebola virus, Zika virus, Severe Acute Respiratory Syndrome (SARS) coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus, and the novel coronavirus (SARS-CoV-2) currently widespread in humans, also infect host cells through membrane fusion. Viral membrane fusion is mediated by fusion proteins located on the surface of viral particles, such as the gp41 subunit of the HIV envelope protein and the S2 subunit of the coronavirus spike S protein. In terms of sequence structure, fusion proteins typically contain important functional regions such as a fusion peptide (FP), heptad repeat domain 1 (HR1), heptad repeat domain 2 (HR2), and a transmembrane domain (TM) in sequence. During the viral membrane fusion process, the fusion protein typically undergoes abrupt conformational changes. First, the FP is exposed and inserted into the target cell membrane; then, HR1 forms a trimer helix, and HR2 folds inverted at the groove formed by the HR1 trimer, forming a typical six-helix bundle (6-HB) structure. This brings the viral membrane and the cell membrane into close proximity, allowing the viral genetic material to enter the target cell through the fusion pore. It has been revealed that polypeptides derived from the HR1 and HR2 regions of many viruses can act as inhibitors of viral membrane fusion by competitively binding to the fusion protein in the pre-fusion state and blocking the formation of the 6-HB structure. Currently, T20 (enfuvirtide), an HIV treatment drug, is the only viral membrane fusion inhibitor approved by the U.S. FDA for clinical use. However, the development of targeted antiviral drugs is always emphasized. To improve the half-life and antiviral activity of polypeptides, modified lipopeptides based on lipid compounds such as fatty acids and cholesterol have become a major direction in the development of viral membrane fusion inhibitors in recent years (see Reference 1). Coronaviruses (CoVs) are envelope-positive single-stranded RNA viruses belonging to four genera: α, β, γ, and δ. CoVs known to infect humans currently include HCoV-229E and HCoV-NL63 of the α genera, and HCoV-OC43, CoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2 of the β genera. HCoV-229E, HCoV-NL63, HCoV-OC43, and CoV-HKU1 are common epidemic pathogens that typically cause common cold symptoms and account for about 10% to 30% of upper respiratory infections in adults; however, they can still cause severe and even fatal disease in children, the elderly, and immunocompromised patients. SARS-CoV, MERS-CoV, and SARS-CoV-2 are classified as highly pathogenic pathogens that cause severe lung disease and have high mortality rates. SARS-CoV-2 shares 79.5% sequence homology with SARS-CoV and 96% with the bat coronavirus SL-CoV-RaTG13, respectively, and uses the same cell receptor (ACE2). However, SARS-CoV-2 is more transmissible than SARS-CoV. By the end of January 2022, nearly 360 million cumulative cases of novel coronavirus (COVID-19) had been reported globally, and more than 5.6 million patients had died (www.who.int). During the pandemic, SARS-CoV-2 has continuously produced variants of concern (VOCs), such as alpha, beta, gamma, delta, omicron, and other viral strains, which often lead to reduced or even inactivated activity of vaccines and drugs. Therefore, there is a need to develop highly effective and broad-spectrum coronavirus inhibitors. In other words, there is a need to develop highly efficient and broad-spectrum coronavirus inhibitors in the field. Inhibitors can suppress various types of coronavirus, including several variants. The research team of the present disclosure is dedicated to the research and development of viral membrane fusion inhibitors and has designed several broad-spectrum coronavirus membrane fusion inhibitors based on lipopeptides. The inhibitors have potent inhibitory activity against SARS-CoV-2 and its mutant strains (see References 2 to 5). When designing lipopeptide-based viral membrane fusion inhibitors, it is often necessary to incorporate a linker between the polypeptide sequence and lipid groups (e.g., fatty acids and cholesterol) to act as a linking arm. The expected binding sites of lipid groups are the virus or cell membrane, whereas polypeptides are abundant in the target region. Therefore, lipid groups and polypeptides have different binding sites. Since polypeptides tend t