The Fight Against Zika: PII

  • In-progress Drugs

    There is an urgent need for broad-spectrum antiviral drugs to treat infections caused by emerging arboviruses. Some experts believe that one medicine for one type of vector insect is not enough to deal with outbreaks like the ZIKV pandemic. However, dozens of antiviral drugs, including virus-targeted drugs, host-targeted drugs, and monoclonal antibodies, have been evaluated in preclinical and early clinical studies, indicating that it is feasible to develop safe and effective anti-ZIKV therapies.

    So far, there is no specific treatment or vaccine for Zika virus disease. Adult patients have mild symptoms and mainly adopt comprehensive symptomatic treatments. Animal experiments showed that drugs such as ribavirin and interferon can inhibit flaviviruses, and whether they can inhibit ZIKV still needs to be studied. Convalescent serum of patients with Zika virus disease contains a large number of neutralizing antibodies. Experiments showed that injecting such convalescent serum into pregnant mice can inhibit the replication of ZIKV in mice and the death of mouse fetal nerve cells, suggesting that specific neutralizing antibodies may have the ability to treat Zika virus disease.

    In recent years, relative success has been achieved in the treatment of hepatitis C that is also caused by Flaviviridae, indicating that it may also have similarly active antiviral potential in the prevention and treatment of ZIKV infection. Anti-HCV therapeutic drugs can target specific viral proteins, including polymerase NS5B, viral RNA binding protein NS5A, or viral protease NS3. Specific anti-ZIKV drugs may target homologous proteins in ZIKV by repositioning anti-HCV drugs. In addition, viral entry or fusion inhibitors and host-directed antiviral therapy will also become promising treatments. In addition, viral entry/fusion inhibitors and host-directed antiviral therapy are also promising treatments.

    Potential antiviral drugs for different stages of the ZIKV life cycle
    Emricasan targets caspase-3 activity to prevent cell death.
    Z2 peptide targets the entering stage of ZIKV into cells.
    5-hydroxycholesterol and chloroquine interfere with lipid homeostasis and autophagy, thereby disrupting the release of viral particles after endocytosis.
    Temoporfin, Nitazoxanide, Niclosamide, and Viperin block NS2B/NS3 protease activity to prevent virus replication.
    Sofosbuvir, Merimepodib, N-(4-hydroxyphenyl) retinamide, 7-deaza-2'-C-methyladenosine, NITD008, BCX4430, and Ribavarin block the activity of ZIKV NS5 polymerase to prevent virus replication.
    Ribavarin and Merimepodib block hypoxanthine nucleotide dehydrogenase.
    Niclosamide, EGCG, and Cavinafungin block CDK to prevent virus replication.

    Some anti-ZIKV small molecule drugs that show activity in animals

    Viral RNA replication and translation inhibitors
    Sofosbuvir, Temoporfin, 7-deaza-2'-C-methyladenosine, BCX4430, Ribavirin, NITD008, NSC157058, Novobiocin, Emetine, Cephaeline

    Inhibitor of virus-host cell interaction
    Peptide Z2

    Inhibitors of autophagy and membrane fusion
    Chloroquine, 25-Hydroxycholesterol

    The R&D of anti-ZIKV drugs has years of history, obtaining various drug candidates with in vivo or in vitro activity by now, but there are only a few drugs that have actually entered clinical trials. According to the Integrity (search date: December 9, 2020), almost all anti-ZIKV drugs in the clinical stage worldwide are vaccines, and there are only 4 therapeutic drugs entering clinical research, namely small molecule drug HSRx-431 and biological drugs INO-A002, Tyzivumab, and ZIKV-IG.

    VRC-5283 (Vaccine)
    mRNA-1325 (Vaccine)
    ChAdOx1 Chik (Vaccine)
    ChAdOx1 Zika (Vaccine)
    GLS-5700 (Vaccine)
    JNJ-66684657 (Vaccine)
    KD-406 (Vaccine)
    mRNA-1893 (Vaccine)
    MV-Zika (Vaccine)
    MV Zika RSP (Vaccine)
    rZIKVD4del30-713 (Vaccine)
    TAK-426 (Vaccine)
    VLA-1601 (Vaccine)
    VRC-5288 (Vaccine)
    ZPIV (Vaccine)
    MVA-ZIKV-NS1 (Vaccine)
    pVAX-tpaNS1 (Vaccine)
    SCV-1002 (Vaccine)
    VBI-2501 (Vaccine)
    Zikavac (Vaccine)
    ZIKV E Vaccine (Vaccine)
    948114 (Vaccine)

    Since the broke out of ZIKV on a global scale in 2015 causing a series of congenital neurological defects, researchers have conducted a lot of studies on ZIKV biology, etiology, epidemiology, pathogenic mechanism, and vaccine development. Effective methods and approaches to prevent and treat ZIKV are still under exploration.