Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

Abstract

Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

Keywords: antiherpetic drugs; bioactive natural products; drug development; drug resistance; herpes simplex virus infection; mechanisms of action; preclinical and clinical studies.

Figure 1

A graphical illustration shows the epidemiology and pathogenesis of herpes simplex virus (HSV) infection. Detailed descriptions are discussed in Section 2.

Figure 2

Phenolic compounds with antiherpetic activity.

Figure 2

Phenolic compounds with antiherpetic activity.

Figure 2

Phenolic compounds with antiherpetic activity.

Figure 3

Alkaloids with antiherpetic activity.

Figure 4

Terpenoid compounds with antiherpetic activity.

Figure 5

Miscellaneous compounds with antiherpetic activity.

Figure 6

The two-dimensional (2D) interaction diagram of 62 in the active cavity of HSV-2 protease. Only those amino acid residues implicated in the enzyme stabilization are exposed. Hydrogen bonding and several substantial interactions with amino acid residues are displayed. This figure and its description have been adapted from Hassan et al. [57] with permission, as the article has been published by an MDPI publisher and licensed under an open access Creative Commons CC BY 4.0 license.

Figure 7

Molecular interaction of psoromic acid (PA, 45) with the active site of HSV-1 DNA polymerase. Amino acid residues involved in HSV-1 DNA polymerase stabilization along with the hydrogen bonding and other essential interactions for enzyme inactivation are presented. The key functional groups of PA that are responsible for anti-HSV-1 DNA polymerase activity are depicted. This figure and its description have been adapted from Hassan et al. [46] with permission, as the article has been published by an MDPI publisher and licensed under an open access Creative Commons CC BY 4.0 license.

Figure 8

Molecular interaction of psoromic acid (PA, 45) with the active site of HSV-2 protease. Amino acid residues involved in HSV-2 protease stabilization along with the hydrogen bonding and other essential interactions for enzyme inactivation are illustrated. Significant functional groups of PA that account for the inhibitory action against HSV-2 protease are presented. This figure and its description have been adapted from Hassan et al. [46] with permission, as the article has been published by an MDPI publisher and licensed under an open access Creative Commons CC BY 4.0 license.

Figure 9

An infographic illustrates the potential mechanisms by which bioactive natural products induce antiviral properties against HSV infection.