Drug Repurposing with Tetracycline and Kampo Medicine (Sho-Sai-Koto and Saiko-Keishi-to) for Crimean-Congo Hemorrhagic Fever: Predicting Efficacy Through In Silico Studies

The Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne bunyavirus that causes acute febrile illness with myalgia, dizziness, neck pain and headache and is associated with a high mortality rate in humans. It extends across vast regions of Africa, Asia, the Middle East, and Southern Europe. CCHFV belongs to the Nairovirus genus of the Bunyaviridae family, which is an enveloped virus with a tri-segmented negative-sense, single-stranded RNA genome, comprising small (S), medium (M), and large (L) segments. The S segment encodes the nucleoprotein (NP). Recent studies have shown that the CCHFV NP, a crucial protein in viral replication, may be considered a potential target for antiviral drug discovery strategies. This protein encapsulates the viral genome and forms a ribonucleoprotein complex, resulting in viral replication. Therefore, inhibition the binding between this protein and viral RNA impairs the replication. Currently, no specific antiviral drugs have been approved for the treatment of CCHFV infection. According to guidelines from the World Health Organization and the Centers for Disease Control and Prevention, treatment is limited to supportive care, including fluid balance control, hydration, fresh frozen plasma, appropriate therapy for secondary infection, and blood transfusions in hemorrhagic cases. Several reports discuss the use of type I interferon, immunoglobulin M antibodies, and ribavirin, but their efficacy is not supported by evidence [1]. Recently, a high-affinity small protein, known as Affimer, specifically binds to the CCHFV NP, thereby blocking viral RNA interaction and inhibiting viral replication in vitro in a mini-genome system [2]. Recent studies on CCHF indicate that vaccines targeting the GP38 glycoprotein of the virus can protect mice from lethal infection, making it a strong candidate for future human vaccines [3]. The absence of an effective drug underscores the need to develop effective treatments against CCHFV and initiate clinical trials to assess their efficacy. Drug repurposing is a well-established strategy for redeploying existing licensed drugs for newer indications, enabling the shortest possible transition from the bench to the bedside. Computational screening through in silico studies offer a cost-effective and time-efficient approach to identifying potential drug candidates for repurposing. This approach demonstrated that tetracyclines, such as doxycycline and minocycline, bind to the CCHFV NP and disrupt the interaction between viral RNA and NP, likely inhibiting CCHFV replication [1]. Subsequently, Hirano et al. demonstrated that tigecycline, another tetracycline, disrupted the interaction between CCHFV NP and viral RNA in vitro [4]. Given their antiviral and anti-inflammatory effects, tetracyclines have already been prescribed or proposed for various viral infections, such as COVID-19, influenza, and Mpox [5,6,7,8]. In another in silico study, Hashim et al. demonstrated that the beta-receptor blocker nebivolol and the antihistamine loratadine have the potential to bind to the RNA-binding region on the CCHFV NP and interfere with virus replication [9].

Furtheremore, another in silico study on phytochemicals demonstrated that skullcapflavone I, niazirin, and withanolide E have binding affinities with the CCHFV NP [10]. Scutellaria, which contains skullcapflavone I in its extracts, is a component of the Kampo medicines (KMs) Shosaiko-to and Saiko-keishi-to [7,11]. KM is a traditional Japanese medicine primarily consisting of organic plant-based ingredients, such as Scutellaria, Ziziphus jujuba, Bupleurum, Glycyrrhiza, and others [7]. Due to their antiviral and anti-inflammatory properties, Shosaiko-to and Saiko-keishi-to have already been prescribed for the treatment of COVID-19 and influenza in Japan [5,6,7]. These findings suggest that the two KMs may be efficacious against CCHFV. There are approximately 150 types of KM that can be commercially prescribed in Japan. KMs are low-priced and are routinely prescribed by clinicians in Japan for various diseases, including pulmonary diseases, hepatic diseases, urological diseases, menopausal disorders, dementia, and others. Moreover, they are known to cause fewer adverse reactions than Western medicines. Based on these results, the aforementioned drugs, particularly tetracyclines and KMs, may be recognized as CCHFV inhibitors in the near future, following in vitro and in vivo testing.