fmicb-11-00139 February 7, 2020 Time: 15:12 # 1 REVIEW published: 11 February 2020 doi: 10.3389/fmicb.2020.00139 Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection Diana M. Álvarez1, Estefanía Castillo1, Luisa F. Duarte1, José Arriagada1, Nicolás Corrales1, Mónica A. Farías1, Adolfo Henríquez2, Cristian Agurto-Muñoz2,3 and Pablo A. González1* 1 Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile, 2 Centro de Biotecnología, Universidad de Concepción, Concepción, Chile, 3 Departamento de Ciencia y Tecnología de Alimentos, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent within the human population and are characterized by lifelong infections and sporadic recurrences due to latent neuron infection. Upon reactivations, HSVs may manifest either, symptomatically or asymptomatically and be shed onto others through mucosae body fluids. Although, HSVs can produce severe disease in humans, such as life- Edited by: threatening encephalitis and blindness, the most common symptoms are skin and Michael Nevels, mucosal lesions in the oro-facial and the genital areas. Nucleoside analogs with antiviral University of St Andrews, activity can prevent severe HSV infection, yet they are not very effective for treating skin United Kingdom manifestations produced by these viruses, as they only reduce in a few days at most Reviewed by: David Leib, the duration of lesions. Additionally, HSV variants that are resistant to these antivirals Dartmouth College, United States may arise, especially in immunosuppressed individuals. Thus, new antivirals that can Guangdi Li, Central South University, China reduce the severity and duration of these cutaneous manifestations would certainly be *Correspondence: welcome. Here, we review currently available anti-herpetic therapies, novel molecules Pablo A. González being assessed in clinical trials and new botanical compounds reported in the last [email protected] 20 years with antiviral activities against HSVs that might represent future treatments Specialty section: against these viruses. This article was submitted to Keywords: HSV-1, HSV-2, natural antiviral compounds, antiviral extracts, phytopharmaceuticals, therapy Virology, a section of the journal Frontiers in Microbiology INTRODUCTION Received: 28 October 2019 Accepted: 21 January 2020 Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 virus (HSV-2) are viruses Published: 11 February 2020 belonging to the Herpesviridae family, Alphaherpesvirinae subfamily and Simplexvirus genus. Citation: HSV-1 and HSV-2 belong to the same family and subfamily than varicella zoster virus (VZV), Álvarez DM, Castillo E, Duarte LF, yet VZV belongs to the Varicellovirus genus (McGeoch, 2009; Kinchington et al., 2012; Ibáñez Arriagada J, Corrales N, Farías MA, Henríquez A, Agurto-Muñoz C and et al., 2018). HSV-1 and HSV-2 are highly prevalent in humans, with global infections ranging González PA (2020) Current Antivirals 70 and 10% of the world population, respectively (Smith and Robinson, 2002; Schillinger et al., and Novel Botanical Molecules 2004; Looker et al., 2008; Chayavichitsilp et al., 2009; Doi et al., 2009) (World Health Organization, Interfering With Herpes Simplex Virus Regional Estimates1. Infection. Front. Microbiol. 11:139. doi: 10.3389/fmicb.2020.00139 1http://www.who.int/mediacentre/news/releases/2015/herpes/en/ Frontiers in Microbiology| www.frontiersin.org 1 February 2020| Volume 11| Article 139 fmicb-11-00139 February 7, 2020 Time: 15:12 # 2 Álvarez et al. Antivirals Against HSV Infection HSV-1 and HSV-2 can cause severe disease in (Perna et al., 1987; Rand et al., 1990). Upon viral reactivation, immunocompetent adults and newborns, such as life-threatening virions travel in a retrograde manner from the cell body of encephalitis with sequelae, despite antiviral treatment (Whitley infected neurons in the trigeminal ganglia (orofacial infection), et al., 2007; Xu et al., 2007; Dinh et al., 2008; Handel et al., 2011). or the dorsal root ganglia (genital-associated infection), to sites These viruses can also produce eye infections leading to visual neighboring epithelial cells and fibroblasts, nearby the original impairment: currently, HSV-1 is the main cause of infectious site of infection, forming new lesions that will repeat the process blindness in developed countries (Farooq and Shukla, 2012). of additional neuron infection (Stevens and Cook, 1971; Lafferty However, the most common clinical manifestations associated et al., 1987; Benedetti et al., 1994). Given this scenario, it seems to HSV-1 and HSV-2 infections are herpes labialis and herpes important to block neuron infection by HSV-1 and HSV-2 during genitalis (Lafferty et al., 1987; Mertz et al., 1998; Kaye and primary infection or to treat neurons in such a way that these Choudhary, 2006; Paz-Bailey et al., 2008; Farooq and Shukla, viruses do not reactivate from these cells. However, a prophylactic 2012), which are characterized by the appearance of vesicular approach for HSV-1 and HSV-2 is yet not available in the form of ulcers in the oro-facial and genital areas that gradually dry out a vaccine (Kwant and Rosenthal, 2004; Belshe et al., 2012) and into crusts and may last up to 14 days during primary infections the effective eradication of these viruses from neurons requires and approximately 10 days during recurrences if no treatment further research (van Diemen et al., 2016; van Diemen and is undertaken (Arduino and Porter, 2007). Lesion development Lebbink, 2017; Chen et al., 2018). is sequential and begins with a prodrome displaying erythema, At present, there are several commercially available antivirals then papules emerge which may progress into vesicles that to treat skin lesions caused by HSV-1 and HSV-2. However, break up giving way to the formation of ulcers. Finally, these such drugs are somewhat ineffective for this type of clinical ulcers dry out forming scabs, which are accompanied by residual manifestation, as they only shorten the recovery time of the swelling and finally healing (Spruance et al., 1977; Corey et al., lesions in 1–2 days in most cases (Evans et al., 2000; Leflore et al., 1983; Fatahzadeh and Schwartz, 2007). The lesions contain 2000). For some individuals, the effectiveness of these treatments high amounts of virions and infiltrating leukocytes and may may be imperceptible [meta-analysis: Chen et al.(2016)]. be painful with a burning sensation, ultimately impacting the On the other hand, approximately 3.5–10% of quality of life of the affected individuals (Spruance et al., 1977; immunosuppressed individuals (e.g., transplanted persons, Dreno et al., 2012). HIV-positive individuals, those undergoing pharmacological Nevertheless, not all the individuals infected with HSV-1 treatments to depress the immune system, among others) may and HSV-2 manifest symptoms. It is estimated that herpetic develop HSV-1 and HSV-2 variants that are resistant to the recurrences due to HSV occur within a wide range of frequencies, most commonly used antivirals (Stranska et al., 2005; Ziyaeyan varying between 20–50% and 80–90% for HSV-1 and HSV-2 et al., 2007; Suazo et al., 2014; Lolis et al., 2016). Although infections, respectively after primary infection (Mertz et al., 1992; second line antivirals exist for these drug-resistant isolates, Benedetti et al., 1994; Cowan et al., 1994; Fleming et al., 1997). such as for acyclovir-resistant variants, unfortunately most of This means that 50–80% and 10–20% of individuals with HSV- these compounds elicit numerous adverse effects (discussed 1 and HSV-2 infection, correspondingly will not show clinical below) (Javaly et al., 1999). In immunocompetent individuals, symptoms of infection. Yet, it is important to note that these drug-resistant variants such as acyclovir-resistant isolates may persons will nevertheless shed infectious viral particles from the also occur, yet at a lower frequency (approximately 1% of cases) mucosae, which could infect other individuals (Johnston and (Bacon et al., 2002; Stranska et al., 2005; Ziyaeyan et al., 2007). Corey, 2015; Ramchandani et al., 2017). On the other hand, up Although this number seems small, considering the significant to one-third of the persons that have had clinical symptoms number of individuals infected with HSV-1 and HSV-2, the during primary infection show frequent reactivations, which figure is substantial. occur on average six times a year (Benedetti et al., 1994). Overall, Several natural products have shown antiviral effects against it is currently estimated that 10–25% of the individuals that HSV-1 and HSV-2, such as extracts, fractionated compounds are infected with HSV manifest disease symptoms, particularly and isolated molecules originated from marine organisms, skin lesions in various forms (herpes labialis, herpes genitalis, microorganisms, fungi, animals, algae and plants, among others eczema herpeticum, zosteriforme herpes, etc.) (Mertz et al., (Hassan et al., 2015). Among these bioactive products there 1992; Cowan et al., 1994; Fleming et al., 1997). Taking into are marine-derived nucleosides, such as spongothymidine and consideration the numbers outlined above, approximately 16 and spongouridin, which gave origin to the first nucleoside analog 5% of the world population will manifest herpetic