Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

Abstract

Approximately 80% of adults are infected with a member of the herpesviridae family. Herpesviruses establish life-long latent infections within neurons, which may reactivate into lytic infections due to stress or immune suppression. There are nine human herpesviruses (HHV) posing health concerns from benign conditions to life threatening encephalitis, including cancers associated with viral infections. The current treatment options for most HHV conditions mainly include several nucleoside and nucleotide analogs targeting viral DNA polymerase. Although these drugs help manage infections, their common mechanism of action may lead to the development of drug resistance, which is particularly devastating in immunocompromised patients. Therefore, new classes of drugs directed against novel targets in HHVs are necessary to alleviate this issue. We analyzed the conservation rates of all proteins in herpes simplex virus 1 (HHV-1), a representative of the HHV family and one of the most common viruses infecting the human population. Furthermore, we generated a full-length structure model of the most conserved HHV-1 protein, the DNA packaging terminase pUL15. A series of computational analyses were performed on the model to identify ATP and DNA binding sites and characterize the dynamics of the protein. Our study indicates that proteins involved in HHV-1 DNA packaging and cleavage are amongst the most conserved gene products of HHVs. Since the packaging protein pUL15 is the most conserved among all HHV-1 gene products, the virus will have a lower chance of developing resistance to small molecules targeting pUL15. A subsequent analysis of the structure of pUL15 revealed distinct ATP and DNA binding domains and the elastic network model identifies a functionally important hinge region between the two domains of pUL15. The atomic information on the active and allosteric sites in the ATP- and DNA-bound model of pUL15 presented in this study can inform the structure-based drug discovery of a new class of drugs to treat a wide range of HHVs.

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

“…Multitargeting strategies may be considered optimal. In addition to polymerases, promising targets include methyltransferases and new viral enzymes such as DNA packaging terminase, which have not yet been targeted by NAs [ 171 ]. Involving host cell enzymes in metabolism to the active form remains a key strategy for reducing toxicity and expanding the spectrum of action.…”

A Protein Assembly Hypothesis for Population-Specific Decrease in Dementia with Time

“…This aspect is analogous to what occurs with both phage T3, and all other studied doublestranded DNA phages. Each of the major herpesvirus proteins involved is homologous to the phage counterpart [12,[20][21][22][23][24]. For developing a hypothesis, this is a pivotal point because phage assembly generated particles are generally more accessible than those of eukaryotic virus counterparts.…”

Compartmentalized Neuronal Culture for Viral Transport Research

“…HSV and VZV are prevalent and important human pathogens with seroprevalence of ~80% in adults (Thaljeh et al, 2019 ). HSV-1 causes cold sores; it replicates in mucosal epithelia and is transmitted to nerve endings.…”