JP-7856325-B2 - Compounds and methods for preventing and treating viral infections

Inventors

• ウー，イェー ビー
• ロ，ジャー－メン
• ホアン，チェン
• リアン，ホイ－ジュ
• リン，ペイ－シン
• チャン，ハオ
• チュウ，ウェイ－チョン
• ホアン，グアン－ジョン

Assignees

• アージル・バイオテック・ホールディング・カンパニー・リミテッド

Dates

Publication Date

20260511

Application Date

20210827

Priority Date

20200828

Claims (1)

1. A pharmaceutical composition for inhibiting cysteine protease in SARS-CoV-2 , comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a mixture thereof, wherein the compound is Formula VI: Compounds having the structure, Formula VII: Compounds having the structure of formula VIII: A pharmaceutical composition, which is one selected from the group consisting of compounds having the structure.

Description

(Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application 63/071,564, filed on 28 August 2020. (Field of invention) The present invention relates to a group of antiviral compounds and methods, as well as combinations/compositions/pharmaceutical compositions, for preventing and treating viral infections, particularly diseases caused by coronaviruses or hepatitis viruses. Viruses are genetic material enclosed in a protein membrane. They invade living, normal cells, and use those cells to multiply and produce other viruses similar to themselves. This can cause common infectious diseases such as influenza and warts, as well as serious diseases like smallpox and acquired immunodeficiency syndrome (AIDS). For example, hepatitis viruses have five distinct types: A, B, C, D, and E, as well as types X and G. Hepatitis A and E are triggered by ingesting contaminated water or food. However, hepatitis B, C, and D are caused by parenteral contact with infected bodily fluids. Furthermore, hepatitis C and D virus infections are increasing, and effective treatment is needed. Hepatitis B virus (HBV) causes acute and chronic viral hepatitis in humans. HBV infection is often associated with severe liver disease, including cirrhosis and hepatocellular carcinoma (HCC) [1]. The prevalence of HBV infection worldwide is very high. Despite effective vaccines being available for more than 25 years, approximately 350 million people remain chronically infected. The relative risk of HCC in HBV carriers is about 100 times higher than in non-carriers [2]. Currently approved anti-HBV drugs, such as interferon-alpha or nucleoside (nucleotide) analogs that inhibit the viral reverse transcriptase, cannot be used in the growing number of HBV-infected patients due to side effects and the development of drug resistance. [3] Therefore, to improve treatment outcomes, it is necessary to search for effective, safe, and reasonably priced anti-HBV drugs that aim to disrupt other stages of the viral life cycle. HBV is a small DNA virus consisting of a nucleocapsid protecting a 3.2 kb viral genome [4]. The HBV nucleocapsid is enclosed in an envelope consisting of the hepatitis B surface antigen (HBsAg). HBsAg is encoded within a single read frame having three in-phase start codons. MHBsAg has a 55 amino acid (aa) extension from the S domain, which is called the pre-S2 domain. LHBsAg has a further 108-aa region extending from the pre-S2 domain, constituting the pre-S1 domain. Recently, sodium-taurocholic acid cotransport polypeptide (NTCP) has been identified as an HBV receptor [5, 6]. HBV entry into uninfected hepatocytes has long been proposed as a potential target for antiviral interventions [7]. On the other hand, HepG2.2.15 cells contain the entire HBV genome and have been widely used in studies of HBV replication, assembly, and secretion. The attachment of HBV to hepatocytes during the infection phase has long been proposed as a potential target for antiviral interventions. Molecules that specifically bind to HBV particles are thought to interfere with viral attachment, thereby reducing or preventing subsequent infection.[8] Knowledge regarding the initial infection event of human HBV is limited due to the lack of cell culture systems that support a complete replication cycle. To date, two cell types have been shown to be susceptible to HBV infection. One is the human hepatocellular carcinoma cell line HepaRG, which becomes infectious after differentiation induced by dimethyl sulfoxide (DMSO) [7,9]. The other is normal human primary hepatocytes, which are readily infected with HBV [10,11]. However, their limited in vitro cell lifespan and lack of a stable supply source significantly limit their future applications. Furthermore, herpes simplex virus (HSV) also consists of a DNA genome enclosed within a protein coat. Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) are causative agents of human diseases including gingivostomatitis, pharyngitis, oral herpes, encephalitis, and infections of the eyes and genitals [12]. Herpesvirus infections generally have a mild or asymptomatic initial stage, after which the virus persists in a non-replicating latent state or at clinically undetectable levels of replication [13]. Primary HSV-1 infections are most associated with the mouth and/or throat, causing gingivostomatitis and pharyngitis. Even after recovering from a primary oropharyngeal infection, individuals may retain HSV DNA in the trigeminal ganglion for life, leading to recurrent outbreaks of oral herpes. Studies have also revealed a possible link between some members of the herpesvirus family and periodontal disease [14]. Human herpesviruses may be present at a relatively high rate in periodontal lesions [15]. HSVs are associated with the severity of periodontal disease in terms of clinical attachment loss [16]. Viral gingival infections can impair the host's defense mechanisms, thereby leadi