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.

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 6 Suchdol 165 21 Prague Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Molecular Biology and Pharmaceutical Biotechnology Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackého tř 1946 1 612 42 Brno Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackého tř 1946 1 612 42 Brno Czech Republic

Division of Oncology Biomedical Center Martin Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Museum of Literature in Moravia Klášter 1 664 61 Rajhrad Czech Republic

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