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CN-118666954-B - Polypeptide for inhibiting replication of herpesvirus and application thereof

CN118666954BCN 118666954 BCN118666954 BCN 118666954BCN-118666954-B

Abstract

The invention discloses a polypeptide for inhibiting herpesvirus replication and application thereof, and belongs to the field of biological medicines. The invention screens out a polypeptide which can specifically interfere the interaction of OTUD4 and USP7, obviously reduce RTA protein level and inhibit the splitting replication of herpesvirus, the amino acid sequence is VNQSASQSSN, and the polypeptide containing the amino acid sequence can be used for preparing anti-herpesvirus medicines or medicines for preventing and treating herpesvirus infection, wherein the herpesvirus is gamma herpesvirus, including KSHV and MHV68.

Inventors

  • ZHANG JUNJIE
  • WANG SHAOWEI
  • Tian Xuezhang
  • ZHOU YARU

Assignees

  • 武汉大学

Dates

Publication Date
20260512
Application Date
20240530

Claims (6)

  1. 1. A polypeptide for inhibiting herpesvirus replication is characterized in that the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1.
  2. 2. A polypeptide for inhibiting herpesvirus replication is characterized in that the amino acid sequence of the polypeptide is shown as SEQ ID NO. 2.
  3. 3. The use of the polypeptide of claim 1 or 2 for preparing an anti-herpesvirus medicament, wherein the herpesvirus is Kaposi's sarcoma virus or murine herpesvirus.
  4. 4. An anti-herpesvirus drug comprising the polypeptide of claim 1 or 2.
  5. 5. The pharmaceutical composition of claim 4, further comprising a pharmaceutically acceptable carrier or excipient.
  6. 6. The medicament according to claim 4 or 5, wherein the herpesvirus is Kaposi's sarcoma virus or murine herpesvirus.

Description

Polypeptide for inhibiting replication of herpesvirus and application thereof Technical Field The invention belongs to the field of biological medicine, and in particular relates to a polypeptide for inhibiting replication of herpesvirus and application thereof. Background Infection with herpes viruses is very common in people and causes a variety of diseases, especially those with low immunity. Herpes viruses are divided into three subfamilies, alpha, beta, gamma, with the Kaposi sarcoma virus (KSHV) belonging to the gamma subfamilies. Like other herpes viruses, the KSHV life cycle is divided into a latency phase and a lytic replication phase. When the virus initiates lytic reactivation, a key viral protein Replication and Transcriptional Activator (RTA) is expressed, and then the RTA binds to the promoter of the viral gene to initiate transcription and expression of a downstream series of genes, thereby bringing the virus into a lytic replication state. The KSHV infection may be followed by a successful escape of human immune system detection, followed by establishment of a long-term latency state. After a specific stimulus to latency infected cells, lytic replication is initiated. KSHV infection replication can lead to the development of a variety of serious diseases such as Kaposi's Sarcoma (KS), primary Exudative Lymphoma (PEL), multiple central vascular follicular lymphoproliferative disorder (MCD), and KSHV-associated inflammatory factor storm (KICS), among others. These diseases are often more frequent in HIV-infected and immunodeficiency patients. Current treatments for KSHV-related diseases have focused mainly on immune-related therapies, such as the CD20 antibody Rituximab, the CD38 antibody Daratumumab, IL-6 antibody Siltuximab, IL-6R antibody Tocilizumab, and therapeutic strategies for HIV-positive patients, such as the PD-1 antibody, CTLA4 antibody. Since no antiviral drug aiming at KSHV itself exists at present, it is extremely important to develop an antiviral drug aiming at KSHV virus lytic replication, and the antiviral drug can be combined with immune related therapy to further promote the therapeutic effect. Since the introduction of insulin in the last century, more than 80 peptide drugs have been marketed, and research into novel peptide therapeutic drugs has been steadily conducted. Currently, more than 150 peptides are in clinical development, and another 400-600 peptides are under preclinical investigation. Can be used for treating various diseases including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. Blocking the binding of viruses to host proteins using polypeptides is a potential approach for the treatment of viral infections. However, this results in the virus producing a series of mutations to escape the treatment of the polypeptide drug, and thus this problem can be solved by blocking the critical host protein complex that regulates viral replication. Ubiquitin-proteasome systems play a key role in controlling target protein stability and regulating various cellular events such as autophagy, DNA damage response, antiviral innate immunity, and viral infection. In earlier studies, we found that the deubiquitinase OTUD4 can bind to KSHV-RTA, promoting deubiquitination and stabilization of RTA, thus promoting KSHV cleavage reactivation (Shaowei Wang et al.,Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases,PLOS PATHOGENS,January 12,2024). it is interesting that the deubiquitinase activity of OTUD4 is not important, instead OTUD4 acts as a linker protein, recruiting another deubiquitinase USP7, increasing the protein level of RTA and promoting KSHV cleavage reactivation. This study reveals a new mechanism, namely that KSHV promotes self-cleavage reactivation using OTUD4-USP7 deubiquitinase, which provides a new target for developing new antiviral therapies. Disclosure of Invention The invention aims to provide a polypeptide for inhibiting replication of herpesvirus and application of the polypeptide in preparation of medicines. The aim of the invention is achieved by the following technical scheme: The invention provides a polypeptide for inhibiting herpesvirus replication, the amino acid sequence of which comprises the sequence shown in SEQ ID NO. 1. SEQ ID NO.1: VNQSASQSSN. Further, the amino acid sequence of the polypeptide for inhibiting herpesvirus replication is shown as SEQ ID NO. 2. SEQ ID NO.2: YGRKKRRQRRRGGVNQSASQSSN. The ubiquitinase OTUD4 promotes the de-ubiquitination and stability of KSHV-RTA by recruiting USP7, thereby promoting KSHV lytic reactivation, and the polypeptide is capable of binding USP7-TRAF, specifically inhibiting the interaction of OTUD4 with USP7, reducing RTA protein stability, thereby inhibiting herpes virus lytic reactivation and lytic replication. The invention also provides application of the polypeptide for inhibiting herpesvirus replication in prepa