viruses Review Current Drugs to Treat Infections with Herpes Simplex Viruses-1 and -2 Lauren A. Sadowski 1,†, Rista Upadhyay 1,2,†, Zachary W. Greeley 1,‡ and Barry J. Margulies 1,3,* 1 Towson University Herpes Virus Lab, Department of Biological Sciences, Towson University, Towson, MD 21252, USA; [email protected] (L.A.S.); [email protected] (R.U.); [email protected] (Z.W.G.) 2 Towson University Department of Chemistry, Towson, MD 21252, USA 3 Molecular Biology, Biochemistry, and Bioinformatics Program, Towson University, Towson, MD 21252, USA * Correspondence: [email protected] † Authors contributed equally to this manuscript. ‡ Current address: Becton-Dickinson, Sparks, MD 21152, USA. Abstract: Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaher- pesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses. Keywords: acyclovir; ganciclovir; cidofovir; vidarabine; foscarnet; amenamevir; docosanol; nelfi- navir; HSV-1; HSV-2 Citation: Sadowski, L.A.; Upadhyay, R.; Greeley, Z.W.; Margulies, B.J. Current Drugs to Treat Infections 1. Introduction with Herpes Simplex Viruses-1 and -2. The world of anti-herpes simplex (anti-HSV) agents took flight in 1962 with the FDA Viruses 2021, 13, 1228. https:// approval of idoxuridine [1,2]. Since then, advances in understanding the genetics of herpes doi.org/10.3390/v13071228 simplex viruses-1 and -2 (HSV-1 and -2) and their enzymology have opened the doors to many new, approved, and active pharmaceuticals, all provided as completely synthetic Academic Editor: Graciela Andrei entities, to treat herpes simplex infections. Received: 24 May 2021 2. HSV-1 and -2 Infection Accepted: 21 June 2021 Published: 25 June 2021 The human herpesviruses HSV-1 and HSV-2 (HSVs) are major human pathogens in the simplexvirus family [3]. Both viruses infect people of all ages, with HSV-1 being more prevalent than HSV-2 [3]; the seroprevalence of the latter tends to increase in different pop- Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in ulations as they age [4]. Once primary infection occurs, these viruses tend to retreat to local published maps and institutional affil- ganglia, where they remain latent for an indeterminant amount of time [3]. Nonetheless, at iations. various times during the life of the host, the latent genomes of these viruses may reactivate and cause productive, lytic infections that may result in clinical signs and symptoms, such as skin lesions, genital sores, keratitis, whitlow, or other mucocutaneous pathologies [3]. In the most extreme cases, HSVs can cause fatal systemic infections or encephalitis, prob- lems typically most associated with immune naïve or immunocompromised patients [3]. Copyright: © 2021 by the authors. Therefore, providing antiviral intervention for those most severely affected by these viruses Licensee MDPI, Basel, Switzerland. This article is an open access article is necessary. distributed under the terms and 3. Nucleoside Analogs conditions of the Creative Commons Attribution (CC BY) license (https:// The majority of anti-HSV drugs are nucleoside analogs that directly target the viral creativecommons.org/licenses/by/ DNA polymerase when in their active form. The virally encoded DNA polymerase pro- 4.0/). vides an essential function, and interfering with this enzyme results in inhibition of viral Viruses 2021, 13, 1228. https://doi.org/10.3390/v13071228 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 12 Viruses 2021, 13, 1228 The majority of anti‐HSV drugs are nucleoside analogs that directly target the2 ofviral 12 DNA polymerase when in their active form. The virally encoded DNA polymerase pro‐ vides an essential function, and interfering with this enzyme results in inhibition of viral DNADNA replication, replication, therefore therefore preventing preventing the the production production of of infectious infectious virions. virions. Although Although this this mechanismmechanism is is effective, effective, a potentiala potential issue issue is that is that these these agents agents could could also target also target the host the DNA host polymeraseDNA polymerase and lead and to lead higher to higher toxicity. toxicity. All nucleoside All nucleoside analogs analogs require require tri-phosphorylation tri‐phosphor‐ beforeylation binding before binding to and inhibiting to and inhibiting the viral the DNA viral polymerase DNA polymerase at its active at its site active [5]. site [5]. TheThe first first phosphorylation phosphorylation of of antiviral antiviral nucleoside nucleoside analogs analogs typically typically occurs occurs via via a a viral viral enzyme,enzyme, thymidine thymidine kinase kinase (TK); (TK); the the subsequent subsequent di- di‐ andand tri-phosphorylations tri‐phosphorylations are are enacted enacted throughthrough cellularcellular kinaseskinases [6[6].]. OneOne benefitbenefit ofof thisthis pathwaypathway isis that that host host toxicity toxicity is is limited limited becausebecause thesethese drugs require the the presence presence of of said said viral viral TK, TK, which which only only appears appears during during the theearly early phase phase of an of active, an active, lytic lytic HSV HSV infection. infection. Without Without the viral the viralTK, these TK, theseanti‐HSV anti-HSV drugs drugstend not tend to not become to become activated activated and therefore and therefore cannot cannot inhibit inhibit any DNA any polymerase. DNA polymerase. None‐ Nonetheless,theless, the host’s the host’s own TK own could TK couldpotentially potentially phosphorylate phosphorylate the drug the first, drug but first, after but cellular after cellularkinases kinasestri‐phosphorylate tri-phosphorylate it, the drug it, will the still drug have will a stillhigher have affinity a higher toward affinity inhibiting toward the inhibitingvirus’ DNA the synthesis virus’ DNA over synthesis that of the over host that [7]. of the host [7]. TheThe main main basis basis for for resistance resistance to nucleoside to nucleoside analogs analogs resides resides in mutations in mutations in TK. Hence,in TK. someHence, antiherpetic some antiherpetic drugs that drugs utilize that a utilize TK-directed a TK‐directed pathway pathway and may and be may less usefulbe less inuseful the facein the of suchface of resistance such resistance include include acyclovir, acyclovir, valacyclovir, valacyclovir, penciclovir, penciclovir, famciclovir, famciclovir, trifluridine, tri‐ idoxuridine,fluridine, idoxuridine, vidarabine, vidarabine, sorivudine, sorivudine, brivudine, brivudine, ganciclovir, ganciclovir, and valganciclovir. and valganciclovir. 4.4. Acyclovir, Acyclovir, the the First First in in Its Its Class Class of of Antiherpetic Antiherpetic Drugs Drugs ManyMany ofof thethe antiherpetic nucleoside nucleoside analogs analogs primarily primarily in in clinical clinical use use are are based based on onthe thecore core structure structure of deoxyguanosine of deoxyguanosine (Figure (Figure 1A).1A). Acyclovir Acyclovir (ACV; (ACV; Figure Figure 1B)1B) is isone one of of the themost most commonly commonly used used of these; of these; it is itactivated is activated by TK by and TK andinhibits inhibits both bothTK and TK DNA and DNA poly‐ polymerasemerase activities. activities. ACV ACV itself itself is a competitive is a competitive inhibitor inhibitor of the of viral the viralTK [8], TK whereas [8], whereas ACV‐ ACV-triphosphatetriphosphate (ACV (ACV-TP)‐TP) acts as acts a competitive as a competitive suicide suicide inhibitor inhibitor for the viral for the DNA viral polymer DNA‐ polymerasease [9]. Although [9]. Although ACV is ACVknown is knownas a chain as a terminator, chain terminator, the nucleotide the nucleotide after ACV after can ACV be canadded be added to the growing to the growing DNA chain, DNA but chain, this but forms this a forms suicide a suicideinhibitor inhibitor complex complex [10] in which [10] inthe which exonuclease the exonuclease activity of activity the DNA of the polymerase DNA polymerase cannot excise cannot ACV excise to ACVrestore to activity; restore activity;HSV DNA HSV polymerase DNA polymerase then gets then caught gets in caught an ever in‐ ancycling ever-cycling trap of adding trap of addinga few nucleo a few‐ nucleotides,tides, excising excising those nucleotides those nucleotides back towards back towards the ACV, the and ACV, repeating and repeating the cycle. the Thus, cycle. the Thus, the inactivation of the viral DNA polymerase prevents the complete replication of inactivation of the viral DNA polymerase prevents the complete replication of the viral the viral genome and subsequently the formation of mature virions [11]. genome and subsequently the formation of mature virions [11]. Figure 1. Nucleoside analogs. Viruses 2021, 13, 1228 3 of 12 ACV toxicity in the host is generally low because of the requirement of viral TK for the first phosphorylation. Nonetheless, host TKs are able to perform the first phosphorylation of ACV at an extremely low