Two metal ion-dependent enzymes as potential antiviral targets for human herpesviruses

Most drug development efforts targeting herpes viruses have focused on nucleoside analogs targeting viral DNA polymerases that have been associated with dose-limiting toxicity and/or narrow-spectrum activity

We are pursuing a strategy that targets two metal ion-dependent (TMID) viral enzymes

Human herpesviruses (HHVs) establish lifelong latent infections that undergo periodic reactivation and remain a major cause of morbidity and mortality, especially in immunocompromised individuals

1), while the prevalence of HSV-2 infection is rising sharply (2) While HSV-1 and -2 are most commonly associated with recurrent oral and genital lesions, they can also cause serious eye infections, end-organ disease, and life-threatening encephalitis

ACV is the first-line antiviral drug for HSV treatment and prevention (three) although long-term use can lead to the development of drug resistance, especially in immunocompromised patients (4–7) viral shedding is frequently observed in immunocompetent individuals treated with ACV, suggesting that current treatment regimens cannot eliminate or completely suppress the virus (8,9).

Most of these essential functions are performed by enzymes involved in viral DNA replication and processing, in particular seven encoded essential DNA replication proteins: polymerase (UL30), polymerase cofactor (UL42), three-subunit helicase / primary enzymes (UL5/UL52/UL8), origin binding protein (UL9),and single-stranded DNA-binding protein (ICP8) (12) In addition, HSV encodes a 5′-3′ alkaline exonuclease UL12, which is essential for viral DNA production (13–16) HHV DNA replication products are longer than the unit-length genomes (concatomers) cleaved by viral terminal enzymes (UL15/UL28/UL33) before embedding (17–19) The largest subunit of this complex, UL15, is responsible for intranuclear cleavage events

Structurally, many of these enzymes are amenable to two metal ion-dependent (TMID) enzymes whose functions include RNA and DNA digestion, DNA integration, and recombination

32,42–44) HIV integrase is a typical RHNL family member (29,30) Influenza endorphinase (PA subunit of viral polymerase) is a member of the DEK family (45–47) Some studies have shown that HIV integrase inhibitors can inhibit the replication of HSV, CMV, Kaposi sarcoma-associated herpesvirus, and feline herpesvirus 1 (twenty three,48,49);However, the molecular targets of its antiviral activity have not been identified
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It has been suggested that integrase inhibitors work by blocking the function of ICP8 and/or UL15 (twenty three,48,49) In this article, we used a candidate-based approach involving multiple metal-directed compounds and several viral enzyme targets in order to correlate targeting activity with antiviral potency
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