Table 1. Main characteristics of studies included in the systematic review.

Main characteristics of studies included in the systematic review

First author

Title

Year

Type of study

Sample characteristics

Intervention

Intervention description

Tested on HSV-1?

Tested on HSV-2?

Tested on VZV?

Tested on resistant strain(s)?

Mutation conferring resistance

Efficacy?

Citation

Agostinho

Cucumis melo pectin as potential candidate to control herpes simplex virus infection

2021

In-vitro

Vero cells

Y

Cucumis melo sulfated pectin

Y

N

N

Y

ACV resistant

Y

[123]

Al-Salahi

Molecular docking study and antiviral evaluation of2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives

2016

In-vitro

Vero cells

Y

Cucumis melo sulfated pectin

Y

Y

N

N

N/A

Y

[10]

Alvarez

Cetylpyridinium chloride blocks herpes simplex virus replication in gingival fibroblasts

2020

In-vitro

Epithelial cells, primary human gingival fibroblasts, Vero cells

Y

Cetylpyridinium chloride (CPC)

Y

Y

N

Y

ACV resistant

Y

[104]

Andrei

The Anti-Human Immunodeficiency Virus Drug Tenofovir, a Reverse Transcriptase Inhibitor, Also Targets the Herpes Simplex Virus DNA Polymerase

2018

In-vitro

Human embryonic lung (HEL) fibroblasts

Y

HSV-1 and  HSV-2 mutants  that are resistance to  tenofovir and  PMEO-DAPy were retested with PMEO-DAPy

Y

Y

N

Y

Tenofovir and PMEO-DAPy–resistant

Y

[49]

Andronova

Study of Antiherpetic Efficiency of Phosphite of Acycloguanosine Able to Overcome the Barrier of Resistance to Acyclovir

2016

In-vivo

Male white mice, male Agouti guinea pigs

Y

Phosphite of acycloguanosine

Y

N

N

Y

ACV resistant HSV-1

Y

[13]

Arunkumar

Study on antiviral activities, drug-likeness and molecular docking of bioactive compounds of Punica granatum L. to Herpes simplex virus - 2(HSV-2)

2018

In-vitro

Human Epidermoid larynx carcinoma cell line

Y

Punica granatum fruit

N

Y

N

N

N/A

Y

[52]

Awad

Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents

2021

In-vitro

Vero cells

Y

In-vitro cyclic and acyclic nucleosies that incorporated 6-substituted- pyrimidine moieties

Y

N

N

N

N/A

Y

[111]

Barboza

In vitro effects of bufotenine against RNA and DNA viruses

2021

In-vitro

N/A

Y

Bufotenine, an alkaloid that can be found in plant extracts and skin secretions of amphibians

Y

N/A

N

Y

ACV resistant HSV-1

N

[126]

Bauer

Antibody-based immunotherapy of acyclovir resistant ocular herpes simplex virus infections

2017

In-vivo

BALB/c mice

Y

Humanized monoclonal antibody (mAb) hu2c that targeted the HSV-1/2 glycoprotein B

Y

Y

N

Y

ACV resistant

Y

[27]

Ben-Amor

Phytochemical Characterization of Olea europea Leaf Extracts and Assessment of Their Anti-Microbial and Anti-HSV-1 Activity

2021

In-vitro

Vero cells

Y

Leaf extracts obtained from Olea europea L. var. sativa (OESA) and Olea europea var. sylvestris (OESY) from Tunisia

Y

N

N

N

N/A

Y

[125]

Benassi-Zanqueta

Evaluation of anti-HSV-1 activity and toxicity of hydroethanolic extractof Tanacetum parthenium (L.) Sch.Bip. (Asteraceae)

2018

In-vitro

N/A

Y

Crude extract of aerial parts of Tanacetum parthenium (L.) Sch.Bip. (Asteraceae), Liquid chromatography-mass spectrometry

Y

N

N

N

N/A

Y

[64]

Benzekri

Anti HSV-2 activity of Peganum harmala (L.) and isolation of the active compound

2017

In-vitro

Vero cells

Y

Methanol Seeds extract, know as alled Peganum harmala

N

Y

N

N

N/A

Y

[32]

Bereczki

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

2020

In-vitro

N/A

Y

Teichoplanins, a glycopeptide antibiotic derivative bearing perfluroroalkyl side chains

Y

Y

N

Y

TK mutation

Y

[89]

Bhutta

Peptide Inhibitor of Complement C1, RLS-0071, Reduces Zosteriform Spread of Herpes Simplex Virus Type 1 Skin Infection and Promotes Survival in Infected Mice

2021

In-vivo

BALB/cJ Mice

Y

RLS-0071, also known as peptide inhibitor of complement C1 (PIC1)

Y

N

N

Y

ACV resistant HSV-1

Y

[134]

Bhutta

Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice

2021

In-vitro

Vero cells

Y

Ginkgolic acid

Y

N

N

Y

ACV resistant HSV-1

Y

[120]

Bisignano

Almond Skin Extracts Abrogate HSV-1 Replication by Blocking Virus Binding to the Cell

2017

In-vitro, experimental study

Vero cells

Y

Extracts with the prevalent compounds quercetin, epicatechin and catechin

Y

N

N

N

N/A

Y

[26]

Bonvicini

Hemidesmus indicus (L.) R. Br. extract inhibits the early step of herpes simplex type 1 and type 2 replication

2018

In-vitro, experimental study

Vero cells

Y

A hydroalcoholic extract from Hemidesmus indicus root

Y

Y

N

N

N/A

Y

[44]

Brenner

The Molecular Tweezer CLR01 Inhibits Antibody-Resistant Cell-to-Cell Spread of Human Cytomegalovirus

2021

In-vitro, experimental study

Human foreskin fibroblasts (HFF)

Y

CLR01

Y

Y

N

Y

Multi-resistant HSV-2

Y

[136]

Brezáni

Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti-Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill

2018

In-vitro

Vero cells

Y

12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. E. Golulus from the Centrum of Medicinal Plants of the Medical Faculty of Masaryk University in Brno

Y

Y

N

N

N/A

Y

[138]

Cagno

In vitro anti-herpes simplex virus-2 activity of Salvia desoleana Atzei & V. Picci essential oil

2017

In-vitro

Vero cells, epithelial cell lines Hep-2

Y

S. desoleana EO, fractions and main components: linalyl acetate, alpha terpinyl acetate, and germacrene D

Y

Y

N

Y

ACV resistant HSV-2

Y

[31]

Castillo

Anti-herpetic Activity of Macrocystis pyrifera and Durvillaea antarctica Algae Extracts Against HSV-1 and HSV-2

2020

In-vitro,     in-vivo

Human cervix epithelial cell line (HeLa cells), primary human gingival fibroblasts, a mouse model

Y

Aqueous extracts obtained from two brown macroalgae, namely Macrocystis pyrifera and Durvillaea antarctica

Y

Y

N

Y

ACV resistant HSV-1

Y

[110]

Chen

Targeting Aryl Hydrocarbon Receptor Signaling Enhances Type I Interferon-Independent Resistance to Herpes Simplex Virus

2021

In-vitro

Human monocytic THP-1 cells, human foreskin fibroblast 1 (HFF-1) cells, Vero cells

Y

Aryl hydrocarbon receptor (AHR) signaling

Y

N

N

N

N/A

Y

[112]

Crameri

MxB is an interferon-induced restriction factor of human herpesviruses

2018

In-vitro

Glioblastoma cells, human lung adenocarcinoma cells, vero cells, HEK-293 cells, and HeLa cells

Y

MxB, protein coded for/released in response to activation of the IFN system

Y

Y

N

N

N/A

PY

[53]

Criscuolo

Synergy evaluation of anti-Herpes Simplex Virus type 1 and 2 compounds acting on different steps of virus life cycle

2018

In-vitro

Vero cells

Y

Pairing viral DNA inhibitors + human IgG mAb

Y

Y

N

N

N/A

PY

[46]

Čulenová

Multiple In vitro biological effects of phenolic compounds from Morus alba root bark

2019

In-vitro

Vero cells

Y

Morus alba L. (compounds from mulberry root bark extract)

Y

Y

N

N

N/A

Y

[85]

D'Aiuto

R430: A potent inhibitor of DNA and RNA viruses

2018

In-vitro

Vero cells and human induced pluripotent stem cells (hiPSC-neurons)

Y

Transdihydrolycoricidine (R430), a lycorane-type alkaloid derivative

Y

Y

N

Y

ACV resistant

Y

[47]

Dai

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

2018

In-vitro

Vero cells

Y

Retro-2.1, an optimized, more potent derivative of Retro-2cyc

N

Y

N

N

N/A

Y

[50]

Dai

Antiviral Effects of ABMA against Herpes Simplex Virus Type 2 In Vitro and In Vivo

2018

In-vitro

Vero cells

Y

The small molecule ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine], acting on host-endosomal trafficking

N

Y

N

N

N/A

Y

[58]

Deback

Antiviral effects of Cacicol (®), a heparan sulfate biomimetic for corneal regeneration therapy, for herpes simplex virus type-1 and varicella zoster virus infection

2018

In-vitro

Vero cells

Y

Cacicol a poly-carboxymethylglucose sulfate solution that is a regernating matrix therapy agent intended for wound healing

Y

N

Y

N

N/A

Y

[60]

Derby

Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo

2018

In-vitro

Vero cells

Y

GRFT Gel for vaginal use

N

Y

N

N

N/A

Y

[45]

Deschamps

Discovery of Small-Molecule Inhibitors Targeting the E3 Ubiquitin Ligase Activity of the Herpes Simplex Virus 1 ICP0 Protein Using an In Vitro High-Throughput Screening Assay

2019

In-vitro

Vero cells

Y

ICP0, a promiscuous transactivator that enables viral gene expression by disrupting DNA repressor complexes and blocking antiviral responses

Y

N

N

N

N/A

Y

[82]

Ding

T-type calcium channels blockers inhibit HSV-2 infection at the late stage of genome replication

2020

In-vitro

Vero cells, HeLa Cells

Y

T-type calcium channel blockers

N

Y

N

N

N/A

Y

[102]

Ding

Cellular Signaling Analysis shows antiviral, ribavirin-mediated ribosomal signaling modulation

2019

In-vitro

Vero cells

Y

Ribavirin-mediated ribosomal signaling modulation, interferons, and S6 kinase inhibitor SL010

Y

N

N

N

N/A

Y

[77]

Donalisio

The traditional use of Vachellia nilotica for sexually transmitted diseases is substantiated by the antiviral activity of its bark extract against sexually transmitted viruses

2017

In-vitro

Vero cells

Y

V. nilotica chloroform, methanolic and water bark extracts

N

Y

N

Y

ACV resistant HSV-2

Y

[39]

Dong

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

2018

In-vitro,     in-vivo

Specific Pathogen-free Chicken Embryo, Vero cells, HEK293Y cells, HeLa cells

Y

Homoharringtonine (HHT)

Y

N

N

N

N/A

Y

[62]

Du

The antiviral activity of arbidol hydrochloride against herpes simplex  virus type II (HSV-2) in a mouse model of vaginitis

2019

In-vivo

Vaginitis animals model

Y

Arbidol (ARB)

N

Y

N

N

N/A

Y

[81]

El-Haddad

Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: A single-center experience

2016

Clinical trial

4 cancer patients with resistant to CMV or HSV infections

Y

Brincidofovir under emergency IND application

Y

N

N

Y

ACV resistant HSV

Y

[1]

El-Shiekh

Novel Antiviral and Antibacterial Activities of Hibiscus schizopetalus

2020

In-vitro

N/A

Y

70% ethanolic extract (Et-E) of the aerial parts of the Hibiscus schizopetalus (Dyer) Hook.f. (Malvaceae), an ornamental plant

N

N

N

N

N/A

Y

[101]

Eletskaya

Enzymatic synthesis of novel purine nucleosides bearing a chiral benzoxazine fragment

2019

In-vitro

N/A

Y

A series of ribo- and deoxyribonucleosides

Y

N

N

Y

Acyclovir-resistant strain of HSV-1

Y

[76]

Elias

In Vitro Analysis of the Antioxidant and Antiviral Activity of Embelin against Herpes Simplex Virus-1

2021

In-vitro

Vero cells

Y

Embelin

Y

N

N

N

N/A

Y

[122]

Fujimoto

Accumulation of a soluble form of human nectin-2 is required for exerting the resistance against herpes simplex virus type 2 infection in transfected cells

2016

In-vitro

Vero cells

Y

A soluble form of human nectin-2 (hNectin-2Ig), transfected cells expressing the entire ectodomain of nectin-2 fused to the Fc portion of human IgG

N

Y

N

N

N/A

Y

[17]

Fujimoto

Evaluation of the antiviral potential of the soluble forms of glycoprotein D receptors on ocular herpes caused by HSV-1 and HSV-2 infections in a transgenic mouse model

2019

In-vivo

Mice

Y

Transgenic mouse serum containing nectin-1Ig

Y

Y

N

N

N/A

Y

[73]

Fujimoto

Comparison of the antiviral potential among soluble forms of herpes simplex virus type-2 glycoprotein D receptors, herpes virus entry mediator A, nectin-1 and nectin-2, in transgenic mice

2017

In-vitro,     in-vivo

Mice

Y

Soluble forms of HVEM, nectin-1 and nectin-2

N

Y

N

N

N/A

Y

[28]

García-Serradilla

Drug repurposing for new, efficient, broad spectrum antivirals

2019

Data Analysis

N/A

Y

Repurposed antiviral drug with different mechanisms of action: digoxin, sunitinib, chloroquine, cyclosporine A and silver nanoparticles in addition to combination therapies with more than one drug

PY

N

N

N

N/A

Y

[65]

Ghaffari

Inhibition of herpes simplex virus type 1 infection by Sambucus ebulus extract in vitro

2021

In-vitro, experimental

Vero cells

Y

Extracts from S. ebulus

Y

N

N

N

N/A

Y

[132]

Ghosh

Ficus religiosa L. bark extracts inhibit infection by herpes simplex virus type 2 in vitro

2016

In-vitro, experimental

Vero cells

Y

F. religiosa extract

N

Y

N

Y

ACV resistant

Y

[20]

González-García

Antimicrobial Activity of Cyclic-Monomeric and Dimeric Derivatives of the Snail-Derived Peptide Cm-p5 against Viral and Multidrug-Resistant Bacterial Strains

2021

In-vitro, experimental

Vero cells, HEK293T cells

Y

Cm-p5 is a snail-derived antimicrobial peptide

N

Y

N

N

N/A

Y

[135]

Greeley

Acyclovir, cidofovir, and amenamevir have additive antiviral effects on herpes simplex virus TYPE 1

2020

In-vitro

Vero cells

Y

(DOE) function in Minitab analyzed the drug-drug interactions of the combination of acyclovir, cidofovir, and amenamevir

Y

N

N

N

N/A

Y

[95]

Hopkins

In Vitro and In Vivo Activity, Tolerability, and Mechanism of Action ofBX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection

2020

In-vitro,     in-vivo

BX795, 8-week-old C57BL/6 female mice

Y

BX795

N

Y

N

N

N/A

Y

[100]

Hou

Antiviral activity of PHA767491 against human herpes simplex virus invitro and in vivo

2017

In-vitro,     in-vivo

L929 cells, 8-week-old RIP3 KO mice

Y

More than 1000 compounds for some antiviral drugs were screened by using the model in which HSV-1 directly induced necrosis of L929

Y

Y

N

N

N/A

Y

[37]

Houston

Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV

2017

In-vitro

Vero cells

Y

Pomegranate rind extract (PRE) was used in conjunction with zinc (II) salts

Y

Y

N

Y

ACV-resistant HSV-2

Y

[30]

Huang

Antiviral activity of mitoxantrone dihydrochloride against human herpes simplex virus mediated by suppression of the viral immediate early genes

2019

In-vitro

Mouse fibroblast cells (L929), Vero cells

Y

Mitoxantrone dihydrochloride (MD)

Y

N

N

N

N/A

Y

[86]

Hutterer

Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases(DYRK) exert a strong anti-herpes viral activity

2017

In-vitro

Human foreskin fibroblasts (HFFs), Vero cells

Y

Novel benzohydrofurane derivatives that target DYRK activity

Y

N

Y

Y

GCV- resistant strain

Y

[38]

Ibáñez

Pharmacological Induction of Heme Oxygenase-1 Impairs Nuclear Accumulation of Herpes Simplex Virus Capsids upon Infection

2017

In-vitro

Vero cells, HeLa cells

Y

Modulating heme oxygenase-1 (HO-1)

N

Y

N

N

N/A

Y

[36]

Ireland

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

2016

In-vitro

Vero cells

Y

Hydroxytropolone pharmacophore

Y

Y

N

Y

(TK)-deficient mutant of HSV-1 and HSV-2

Y

[9]

Ishimaru

MG132 exerts anti-viral activity against HSV-1 by overcoming virus-mediated suppression of the ERK signaling pathway

2020

In-vitro

Vero cells, HepG2, H1299, ME180, MCF7, HeLa cells

Y

Protease inhibitors (TLCK, TPCK, E64, bortezomib, or MG132)

Y

N

N

N

N/A

Y

[99]

Jaishankar

An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye

2018

In-vitro, in-vivo, ex-vivo

Human corneal epithelial (HCE) cells, Mouse model, porcine and human cornea organ culture

Y

BX795 and its potential synergism with trifluridine (TFT)

Y

N

N

N

N/A

Y

[56]

Jin

Pentagalloylglucose Blocks the Nuclear Transport and the Process of Nucleocapsid Egress to Inhibit HSV-1 Infection

2015

In-vitro

Vero cells

Y

Pentagalloylglucose (PGG)-induced inhibition of nuclear transport and nucleocapsid egress

Y

N

N

Y

A TK mutant from HSV-1 and two ACV-resistant clinical HSV-1 strains

Y

[6]

Jones

Modified cyclodextrins as broad-spectrum antivirals

2020

In-vitro

Vero cells

Y

Cyclodextrins modified with mercaptoundecane sulfonic acids

Y

Y

N

Y

ACV resistant HSV-2

Y

[93]

Kalke

Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-TargetedsiRNA Swarm Treatment Independent of Their Acyclovir Sensitivity

2020

In-vitro

Vero cells

Y

Enzymatically synthesized siRNA swarms

Y

N

N

Y

ACV resistant HSV-1

Y

[98]

Kannan

Anti-herpes virus activity of the carnivorous botanical, Sarracenia  purpurea

2020

In-vitro

Vero cells

Y

S. purpurea extract

Y

N

N

N

N/A

Y

[87]

Karpov

[A Plasmid-Expressed CRISPR/Cas9 System Suppresses Replication of HSV Type I in a Vero Cell Culture]

2019

In-vitro

Vero cells

Y

Genome editing via prokaryotic plasmid CRISPR/Cas9

Y

N

N

N

N/A

Y

[79]

Katsumata

Antiviral efficacy of the helicase-primase inhibitor amenamevir in murinemodels of severe herpesvirus infection

2018

In-vivo

Mice

Y

Amenamevir, a helicase-primase inhibitor

Y

N

Y

N

N/A

Y

[43]

Kaushik

Antiviral potential and mode of action of Indigofera heterantha against HSV-2 by targeting the early stages of infection

2016

In-vitro,     in-vivo

Mice and plaque reduction assays

Y

Extract of roots of the plant Indigofera heterantha

N

Y

N

N

N/A

Y

[18]

Kim

Quercus acuta Thunb. (Fagaceae) and Its Component, Isoquercitrin, InhibitHSV-1 Replication by Suppressing Virus-Induced ROS Production and NF-κB Activation

2021

In-vitro

Vero cells

Y

Quercus acuta Thunb (Fagaceae) (QA) extract

Y

N

N

N

N/A

Y

[127]

Kim

Mori ramulus and its Major Component Morusin Inhibit Herpes Simplex Virus Type 1 Replication and the Virus-Induced Reactive Oxygen Species

2020

In-vitro

Vero cells

Y

Mori ramulus (the young twig of Morus alba L.)

Y

N

N

N

N/A

Y

[103]

Kongyingyoes

3,19-isopropylideneandrographolide suppresses early gene expression of drug-resistant and wild type herpes simplex viruses

2016

In-vitro

Vero cells

Y

A diterpenoid lactone, 3,19-isopropylideneandrographolide (IPAD) compound isolated from Andrographis

Y

Y

N

Y

ACV-resistant and (TK) deficient

Y

[14]

Kumar

Inhibition of herpes simplex virus-1 infection by MBZM-N-IBT: in silico and in vitro studies

2021

In-vitro

Vero cells

Y

MBZM-N-IBT impact against HSV-1

Y

N

N

N

N/A

Y

[133]

Labrunie

UL23, UL30, and UL5 characterization of HSV1 clinical strains isolated from hematology department patients

2019

In-vitro

N/A

N

Genetic variants

N

N

N

N

N/A

N

[84]

Le-Trilling

Broad and potent antiviral activity of the NAE inhibitor MLN4924

2016

In-vitro

N/A

Y

NAE inhibitor MLN4924

Y

Y

N

Y

ACV, CDV and PFA resistant HSV-1

Y

[19]

Lebrun

Varicella-Zoster Virus ORF9p Binding to Cellular Adaptor Protein Complex 1Is Important for Viral Infectivity

2018

In-vitro

Yeast cells

N

ORF9p proteins

N

N

N

N

N/A

N

[139]

Lee

Efficacy of brincidofovir as prophylaxis against HSV and VZV in hematopoietic cell transplant recipients

2018

In-vivo

2710 patient-days

Y

Brincidofovir a lipid conjugate of cidofovir

Y

Y

Y

N

N/A

Y

[48]

Lei

Preparation of a monoPEGylated derivative of cyanovirin-N and its virucidal effect on acyclovir-resistant strains of herpes simplex virus type 1

2019

In-vivo

N/A

Y

Cyanovirin-N (CV-N) more specifically LCV-N as the most potent of  three compounds

Y

N

N

Y

ACV resistant

Y

[2]

Li

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

2019

In-vivo

N/A

Y

Amentoflavone, a naturally occurring biflavonoid

Y

N

N

Y

ACV resistant

Y

[67]

Li

Anti-herpes simplex virus type 1 activity of Houttuynoid A, a flavonoidfrom Houttuynia cordata Thunb

2017

In-vitro,     in-vivo

Mice

Y

Houttuynia A cordata Thunb. water extract, a new type of flavonoid isolated from H. cordata

Y

Y

Y

N

N/A

Y

[25]

Liu

Antiviral activities of Janus-type nucleosides and their related oxime-intermediates

2018

In-vitro

Vero cells

Y

Janus-type nucleosides combining the natural genetic alphabets into a singular nucleoside structural unit

Y

N

N

N

N/A

Y

[41]

Liu

Harringtonine Inhibits Herpes Simplex Virus Type 1 Infection by Reducing Herpes Virus Entry Mediator Expression

2021

In-vitro

Vero cells

Y

Harringtonine

Y

N

N

Y

(TK) mutation in HSV-1

Y

[116]

Lopes

Sulfonated and Carboxymethylated β-Glucan Derivatives with Inhibitory Activity against Herpes and Dengue Viruses

2021

In-vitro

Vero cells

Y

(1→3)(1→6)-β-D-glucan, botryosphaeran, similar to an anionic polysaccharide

Y

N

N

Y

ACV resistant

Y

[128]

Luganini

Effective deploying of a novel DHODH inhibitor against herpes simplex type1 and type 2 replication

2021

In-vitro

Vero cells

Y

MEDS433 a pyrimidine synth inhibitor

Y

Y

N

N

N/A

Y

[129]

Ma

Herpes simplex virus type 1 (HSV-1) specific T-cell generation fromHLA-A1- and HLA-A2-positive donors for adoptive immunotherapy

2016

In-vitro

Peripheral blood mononuclear cells from HLA-A1 and HLA-A2 HSV-seropositive hereditary hemochromatosis donors

Y

HSV-1-specific T cells

Y

N

N

N

N/A

Y

[12]

Ma

Assessment of a new arbidol derivative against herpes simplex virus II inhuman cervical epithelial cells and in BALB/c mice

2019

In-vitro

HCE cells

Y

Arbidol derivative (ARD)

N

Y

N

N

N/A

Y

[75]

Maizel

Study of the Extremely-Tolerant Brevibacterium linens AE038-8 with Antiviral Activity Against Herpes Simplex Virus Type 1

2021

In-vitro

N/A

Y

B. linens AE038-8

Y

N

N

Y

ACV resistant

Y

[113]

Mandalari

Simulated human digestion of N1-aryl-2-arylthioacetamidobenzimidazoles and their activity against Herpes-simplex virus 1 in vitro

2019

In-vitro

N/A

Y

NAAB-496 and NAAB-503

Y

N

N

N

N/A

Y

[72]

Marcocci

The Amphibian Antimicrobial Peptide Temporin B Inhibits In Vitro Herpes Simplex Virus 1 Infection

2018

In-vitro

Vero cells, human epithelial cells

Y

Temporin B (TB)

Y

N

N

N

N/A

Y

[54]

Marino-Merlo

Anti-herpes simplex virus 1 and immunomodulatory activities of a poly-γ-glutamic acid from Bacillus horneckiae strain APA of shallow vent origin

2017

In-vitro

HEp-2 cells, U937 cells,

Y

Poly-γ-glutamic acid (γ-PGA-APA)

Y

N

N

N

N/A

Y

[29]

Mello

Perillyl alcohol and perillic acid exert efficient action upon HSV-1maturation and release of infective virus

2020

In-vitro

Vero cells

Y

Monoterpenes perillyl alcohol (POH) and perillic acid  (PA)

Y

N

N

N

N/A

Y

[92]

Mishra

Herbal Gel Formulation Developed for Anti-Human Immunodeficiency Virus(HIV)-1 Activity Also Inhibits In Vitro HSV-2 Infection

2018

In-vitro

Vero cells

Y

Polyherbal gel formulation (aqueous gel formulation comprising of 50% ethanolic extracts prepared from stem bark of Acacia catechu, leaves of Lagerstroemia speciosa, and fruits of Terminalia chebula & Phyllanthus emblica)

N

Y

N

N

N/A

Y

[59]

Mohammed

Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutyl guanine derivatives

2019

In-vitro

Human embryonic lung (HEL) cell, Vero cells, HeLa cells, MDCK cells

Y

Novel tricyclic derivatives

Y

Y

N

Y

ACV resistant, (TK-)

Y

[69]

Monjo

Photodynamic Inactivation of Herpes Simplex Viruses

2018

In-vitro

HeLa, HEK293A, Vero cells

Y

Orthoquin in sub-cytotoxic doses

Y

Y

N

N

N/A

Y

[55]

Moshaverinia

Evaluation of the effect of hydro alcoholic extract of cinnamon on herpes simplex virus-1

2020

In-vitro

N/A

Y

Hydroalcoholic extract of cinnamon

Y

N

N

N

N/A

Y

[94]

Musarra-Pizzo

The Antimicrobial and Antiviral Activity of Polyphenols from Almond(Prunus dulcis L.) Skin

2019

In-vitro

Vero cells

Y

Natural almond skin (NS MIX)

Y

N

N

N

N/A

Y

[68]

Novoa

Antiviral Activity of Myticin C Peptide from Mussel: an Ancient Defense against Herpesviruses

2016

In-vitro

Vero cells

Y

Myticin C Peptide

Y

Y

N

N

N/A

Y

[8]

Paavilainen

Topical treatment of herpes simplex virus infection with enzymatically created siRNA swarm

2017

In-vivo

BALB/c mice

Y

Treated with a swarm of enzymatically created, Dicer-substrate small interfering RNA (siRNA) molecules that targeted the HSV gene UL29

Y

N

N

N

N/A

Y

[22]

Parsania

Antiviral screening of four plant extracts against acyclovir resistant herpes simplex virus type-1

2017

In-vitro

N/A

Y

Methanolic extract of four plants

Y

N

N

N

N/A

Y

[24]

PiresdeMello

Aminomethylnaphthoquinones and HSV-1: in vitro and in silico evaluations of potential antivirals

2016

In-vitro

Vero cells

Y

Three 2-aminomethyl-3-hydroxy-1,4-naphthoquinones

Y

N

N

N

N/A

Y

[3]

Pradhan

Herpes simplex virus virucidal activity of MST-312 and epigallocatechin gallate

2018

In-vitro

N/A

Y

MST-312

Y

N

N

N/A

N/A

Y

[63]

Praena

Amidic derivatives of valproic acid, valpromide and valnoctamide, inhibitHSV-1 infection in oligodendrocytes

2019

In-vivo

Glial cells

Y

Two amidic derivatives of valproic acid (VPA) - valpromide (VPD) and valnoctamide (VCD)

Y

N

N

N

N/A

Y

[78]

Pujol

Polyhydroxylated sulfated steroids derived from 5α-cholestanes as antiviral agents against herpes simplex virus

2016

In-vitro

Human cells lines, vero cells

Y

Twelve polyhydroxylated sulfated steroids synthesized from a 5α-cholestane skeleton with different substitutions in C-2, C-3 and C-6

Y

Y

N

N

N/A

Y

[16]

Quenelle

Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis

2017

In-vitro

Mice

Y

Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir.

Y

Y

N

Y

ACV resistant

Y

[35]

Rechenchoski

Mangiferin: A promising natural xanthone from Mangifera indica for the control of acyclovir - resistant herpes simplex virus 1 infection

2020

In-vitro,     in-vivo

Vero cells

Y

M. Indica (Mangiferin; a mango extract)

Y

N

N

Y

ACV-resistant HSV-1

Y

[106]

Rittà

Antiviral Activity of a Arisaema Tortuosum Leaf Extract and Some of its Constituents against Herpes Simplex Virus Type 2

2020

In-vitro

Vero cells

Y

Arisaema tortuosum, a plant medicine from India

Y

Y

N

Y

Acyclovir-resistant HSV-2

Y

[91]

Ruzsics

A Novel, Broad-Acting Peptide Inhibitor of Double-Stranded DNA Virus Gene Expression and Replication

2020

In-vitro

Vero cells

Y

A novel peptide called TAT-I24

Y

N

N

Y

ACV resistant

Y

[90]

Sacchelli

Botryosphaeran and sulfonated derivatives as novel antiviral agents for herpes simplex and dengue fever

2019

In-vitro

Vero cells

Y

Botryosphaeran, a fungal exocellular (1 → 3)(1 → 6)-β-D glucan devoid of sulfate groups

Y

N

N

N

N/A

Y

[74]

SadeghEhdaei

Cellular miR-101-1 Reduces Efficiently the Replication of HSV-1 in HeLa Cells

2021

In-vitro

HeLa cells

Y

Hsa-miR-101-1

Y

N

N

N

N/A

Y

[114]

Sanchez

Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways

2016

In-vitro

Primary human corneal epithelial cells (HCEC)

Y

A pegylated recombinant human Arginase I (peg-ArgI)

Y

Y

N

Y

Polymerase (PAAr5) or thymidine kinase (tkLTRZ1; tkG7dG.2) genes

Y

[11]

Sasaki

In vitro and in vivo antiherpetic effects of(1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol

2016

In-vitro,     in-vivo

Female BALB/c mice 5–6 weeks old

Y

MFPT

Y

Y

N

Y

ACV resistant HSV-1

Y

[15]

Schneider

Early Steps in Herpes Simplex Virus Infection Blocked by a Proteasome Inhibitor

2019

In-vitro

Vero cells, human foreskin fibroblasts

Y

Bortezomib and many of its property against HSV

Y

Y

N

Y

ACV resistant

Y

[83]

Shabani

Inhibition of herpes simplex virus type 1 replication by novelhsa-miR-7704 in vitro

2019

In-vitro

HeLa cells

Y

A novel miRNA (hsa-miR-7704), expressed in macrophages

Y

N

N

N

N/A

Y

[71]

Shan

Viral UL8 Is Involved in the Antiviral Activity of Oleanolic Acid AgainstHSV-1 Infection

2021

In-vitro

Vero cells, Human immortalized keratinocyte cell line (HaCaT)

Y

Oleanolic acid, a pentacyclic triterpenoid widely existing in natural product

Y

N

N

Y

TK mutant  from HSV-1   and two clinical ACV-resistant HSV-1 strains

Y

[130]

Shao

Poly(dA:dT) Suppresses HSV-2 Infection of Human Cervical Epithelial Cells Through RIG-I Activation

2021

In-vitro

Human endocervical epithelia (End1) cells

Y

Poly (dA:dT) treatment of End1/E6E7 cells

N

Y

N

N

N/A

Y

[124]

Sharifi-Rad

Susceptibility of herpes simplex virus type 1 to monoterpenes thymol, carvacrol, p-cymene and essential oils of Sinapis arvensis L., Lallemantia royleana Benth. and Pulicaria vulgaris Gaertn

2017

In-vitro

Vero cells

Y

Three monoterpenes (thymol, carvacrol and p-cymene) and three essential oils

Y

N

N

N

N/A

Y

[34]

Sharifi-Rad

Antiviral activity of Veronica persica Poir. on herpes virus infection

2018

In-vitro

Vero cells

Y

Veronica persica Poir extract

Y

Y

N

N

N/A

Y

[51]

Shiraki

Helicase-primase inhibitor amenamevir for herpesvirus infection: Towards practical application for treating herpes zoster

2017

N/A

N/A

Y

Helicase-primase inhibitors (HPIs) inhibit the progression of the replication fork ( initial step in DNA synthesis to separate the double strand into two single strands). The HPIs amenamevir and pritelivir have a novel mechanism of action, once-daily administration with nonrenal excretory characteristics, and clinical efficacy for genital herpes.

Y

N

Y

N

N/A

PY

[21]

Shiraki

Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster

2021

N/A

N/A

Y

Amenamevir and synergism with acyclovir.

Y

N

Y

Y

Amenamevir-resistant viruses with changes in the helicase and primase of amenamevir-resistant HSV mutants

Y

[121]

Spengler

Antiviral, Antimicrobial and Antibiofilm Activity of Selenoesters and Selenoanhydrides

2019

In-vitro

Vero cells

Y

Selenoesters and selenium isostere

N

Y

N

N

N/A

Y

[66]

Stegman

Volatile Acid-Solvent Evaporation (VASE): Molecularly Homogeneous Distribution of Acyclovir in a Bioerodable Polymer Matrix for Long-Term Treatment of Herpes Simplex Virus-1 Infections

2018

In-vitro

Vero cells

Y

Bioerodable polymer polycaprolactone

Y

N

N

N

N/A

Y

[40]

Suryawanshi

Bacterial Pigment Prodigiosin Demonstrates a Unique Antiherpes virus Activity That Is Mediated through Inhibition of Prosurvival Signal Transducers

2020

In-vitro, ex-vivo, in-vivo

Human corneal epithelial (HCE) cells, HeLa cells, C57BL/6 mice, porcine corneal model, whole pig eyes

Y

Prodigiosin (PG)

Y

Y

N

N

N/A

Y

[109]

Tavakoli

Inhibition of herpes simplex virus type 1 by copper oxide nanoparticles

2019

In-vitro

Vero cells

Y

Copper oxide nanoparticles (CuO-NPs) on HSV-1 infection

Y

N

N

N

N/A

Y

[70]

Tintori

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

2018

In-vitro

Vero cells, human CD4+ lymphocytes

Y

Rhodanine derivatives

Y

Y

N

Y

ACV resistant HSV-2

Y

[61]

Toscani

Synthesis and Biological Evaluation of Amidinourea Derivatives against Herpes Simplex Viruses

2021

In-vitro

Vero cells

Y

Amidinourea analogues of moroxydine

Y

Y

N

N

N/A

Y

[118]

Toulabi

The efficacy of olive leaf extract on healing herpes simplex virus labialis: A randomized double-blind study

2021

Randomized double-blind clinical trial

66 human patients diagnosed with HSV-1

Y

Comparison of 2% OLE cream or 5% acyclovir cream five times a day for six days

Y

N

N

N

N/A

Y

[119]

Tyo

pH-responsive delivery of Griffithsin from electrospun fibers

2019

In-vitro

Vaginal keratinocyte, endocervical, and ectocervical cells, TZM-bl cell

Y

H-responsive fibers comprised of poly(lactic-co-glycolic acid) (PLGA) or methoxypolyethylene glycol-b-PLGA (mPEG-PLGA) with varying ratios of poly(n-butyl acrylate-co-acrylic acid) (PBA-co-PAA), to selectively release griffithsin (GRFT) under pH-conditions that mimic semen introduction

N

N

N

N

N/A

Y

[80]

Uhlig

Helicase primase inhibitors (HPIs) are efficacious for therapy of human herpes simplex virus (HSV) disease in an infection mouse model

2021

In-vitro,     in-vivo

Female BALB/c mice (8 weeks old), Vero cells

Y

Diverse racemates of the sulfonimidoyl thiazole amide class compounds

Y

Y

N

Y

ACV-resistant HSV-1 and HSV-2

Y

[137]

Urbancikova

Efficacy of Pleuran (β-Glucan from Pleurotus ostreatus) in the Managementof Herpes Simplex Virus Type 1 Infection

2020

Clinical trial

90 human patients over 6years with herpes simplex facialis/labialis

Y

β-glucanpleuran (insolubleβ-1,3/1,6-D-glucan isolated from Pleurotus ostreatus) based supplements

Y

N

N

N

N/A

Y

[88]

Vanheule

Basic chemokine-derived glycosaminoglycan binding peptides exert antiviral properties against dengue virus serotype 2, herpes simplex virus-1 and  respiratory syncytial virus

2015

In-vitro

Chinese Hamster ovary, human embryonic lung and human cervical carcinoma (HeLa) cells

Y

COOH-terminal peptides of CXCL9 and CXCL12γ for their affinity to GAGs and KD values

Y

Y

N

N

N/A

Y

[7]

Viegas

Antiviral activity of 1,4-disubstituted-1,2,3-triazoles against HSV-1 invitro  and effects of amino acid changes in drug-resistant α and βherpesviruses DNA polymerase

2020

In-vitro

Human fibroblast cells

Y

Triazole compounds

Y

N

N

Y

ACV resistant HSV-1

Y

[96]

VilasBoas

Linear antimicrobial peptides with activity against herpes simplex virus 1and Aichi virus

2017

In-vitro

N/A

Y

Various antimicrobial peptides

Y

N

N

N

N/A

Y

[23]

Vilhelmova-Ilieva

Antiviral Activity of Rosa damascena Mill. and Rosa alba L. Essential Oils  against the Multiplication of Herpes Simplex Virus Type 1 Strains Sensitive and Resistant to Acyclovir

2021

In-vitro

Madin-Darby bovine kidney (MDBK) cells

Y

Rosa damascena Mill. and Rosa alba L. essential oils

Y

N

N

Y

ACV resistant

N

[131]

Wang

Guanidine modifications enhance the anti-herpes simplex virus activity of(E,E)-4,6-bis(styryl)-pyrimidine derivatives in vitro and in vivo

2020

In-vitro,     in-vivo

Vero cells

Y

Guanidine-modified (E,E)-4,6-bis(styryl)-pyrimidine (BS-pyrimidine) derivative compound 5d

Y

Y

N

N

N/A

Y

[108]

Wang

Anti-HSV-1 activity of Aspergilli peptide D, a cyclic pentapepetide isolated from fungus Aspergillus sp. SCSIO 41501

2020

In-vitro

N/A

Y

Aspergillipeptide D

Y

N

N

N

N/A

N

[107]

Whitley

Clinical management of herpes simplex virus infections: past, present, and future

2018

N/A

N/A

N

N/A

N

N

N

N

N/A

N/A

[57]

Wright

Inhibition of Herpes Simplex Viruses, Types 1 and 2, by Ginsenoside20(S)-Rg3

2020

In-vitro

Vero cells

Y

Ginsenosides derived from Panax ginseng

Y

Y

N

N

N/A

Y

[105]

Ye

Lupeol impairs herpes simplex virus type 1 replication by inhibiting the promoter activity of the viral immediate early gene α0

2021

In-vitro

N/A

Y

Lupeol, a triterpenoid compound

Y

N

N

Y

ACV resistant

Y

[115]

Zhang

NSC23766 and Ehop016 Suppress Herpes Simplex Virus-1 Replication by Inhibiting Rac1 Activity

2021

In-vitro

Vero cells

Y

Ras-related C3 botulinum toxin substrate 1 Rac1 as a target using Rac1-specific inhibitors, titled  NSC23766 and Ehop016

Y

N

N

N

N/A

Y

[117]

Zhou

Anti-HSV-1 effect of dihydromyricetin from Ampelopsis grossedentata via the TLR9-dependent anti-inflammatory pathway

2020

In-vitro, experimental study

Vero cells

Y

A flavonoid compound dihydromyricetin (DHM) from Ampelopsis grossedentata

Y

N

N

N

N/A

Y

[97]

Zígolo

Chemoenzymatic synthesis of new derivatives of glycyrrhetinic acid with antiviral activity. Molecular docking study

2018

In-vitro, experimental study

Vero cells

Y

Synthesized GA derivative, 4d (N-(3-acetylglycyrrhetinoyl)-2-amino-1-propanol)

Y

N

N

Y

ACV resistant HSV-1

Y

[42]

Zinser

A new promising candidate to overcome drug resistant herpes simplex virus infections

2017

In-vitro, experimental study

Vero cells

Y

Synthesized SC95377

Y

Y

N

Y

ACV and multi-resistant resistant HSV-1 and HSV-2

Y

[33]