Marine Microorganisms and Their Bioactive Compounds as Emerging Antiviral Agents Against Herpes Simplex Virus

Abstract

Herpes Simplex Virus (HSV), comprising HSV-1 and HSV-2, affects billions worldwide, posing a persistent challenge due to its ability to establish latency and evade immune responses. Conventional treatments such as acyclovir are limited to suppressing viral replication during active infection phases, failing to eliminate latent virus or prevent recurrence. As drug resistance and reactivation remain critical issues, alternative antiviral approaches are urgently needed. Marine microorganisms, due to their unique ecological adaptations and biosynthetic capabilities, produce structurally novel and pharmacologically potent the compounds. These marine-derived agents including sulfated polysaccharides, peptides, alkaloids, and terpenoids demonstrate multi-target anti-HSV activity ranging from inhibition of viral entry and replication to immune modulation. This review explores the virology of HSV, limitations of current therapies, and the promise of marine ecosystems as a source of new antiviral agents. It further highlights recent advances in preclinical models, synthetic biology, and the metagenomics that enhance the discovery pipeline. The review concludes by identifying challenges and future directions for translating marine bioproducts into clinically viable antiviral therapies.

Keywords

Introduction

Herpes simplex viruses (HSV-1 and HSV-2) are globally prevalent infections characterized by their lifelong latency and periodic reactivation. Despite available treatments such as acyclovir and valacyclovir, these nucleoside analogs primarily target viral replication but do not eliminate latent infection or prevent recurrence. Emerging drug resistance and limited treatment options for immunocompromised individuals further highlight the need for novel antiviral agents. In recent years, marine environments have drawn the attention as a promising source of unique bioactive compounds. Marine microorganisms, including actinomycetes, fungi, cyanobacteria, and algae, produce structurally distinct secondary metabolites due to their adaptation to extreme habitats. These compounds have shown potential antiviral activities against a various viruses, including HSV. This review aims to explore marine-derived compounds with anti-HSV properties and discusses their mechanisms, efficacy in preclinical studies, and future drug development prospects.

2.0.Virology and Pathogenesis of HSV

HSV-1 typically causes orolabial lesions, while HSV-2 primarily causes genital infections. Both viruses establish latency in sensory neurons after primary infection. Reactivation leads to recurrent lesions and asymptomatic shedding. The virus evades host immunity by downregulating MHC I molecules and interfering with interferon responses. Latency-associated transcripts (LATs) help suppress viral gene expression during dormancy, making therapeutic targeting difficult. Herpes Simplex Viruses (HSV) are double-stranded DNA viruses belonging to the Herpesviridae family, subfamily Alphaherpesvirinae. The two main human pathogenic types - HSV-1 and HSV-2 share about 50–70% genomic similarity but differ in their primary sites of infection and clinical manifestations. HSV-1 predominantly causes orolabial infections, while HSV-2 is more commonly associated with genital lesions, although both can cause disease in either location.

2.1. Structure of HSV

HSV virions are enveloped particles approximately 150–200 nm in diameter. They consist of:

• A core containing a linear double-stranded DNA genome (~152 kb) encoding around 80 genes.
• An icosahedral capsid made of 162 capsomeres.
• A tegument layer containing viral proteins involved in immune evasion and viral replication (e.g., VP16, UL41).

2.2. Viral Entry and Replication

HSV entry is mediated by interactions between viral envelope glycoproteins and host cell surface receptors:

• gD binds to host receptors like nectin-1 or HVEM.
• gB and gH/gL mediate membrane fusion and viral entry.

Following entry, the capsid is transported to the nucleus via microtubules. Viral DNA is released into the nucleus where three temporal classes of genes are expressed:

• Immediate-early (IE) genes (e.g., ICP0, ICP4): Regulate subsequent gene expression and block host defenses.
• Early (E) genes: Involved in DNA replication.
• Late (L) genes: Encode structural proteins.

After genome replication, viral assembly occurs in the nucleus, and virions are transported to the plasma membrane for release.

2.3. Latency and Reactivation

A hallmark of HSV is its ability to establish lifelong latency in sensory ganglia:

• HSV-1 resides in the trigeminal ganglia.
• HSV-2 resides in the sacral ganglia.

During latency:

• The viral genome persists as an episome.
• Only Latency-Associated Transcripts (LATs) are expressed. These non-coding RNAs help suppress lytic gene expression and protect neurons from apoptosis.

2.4. Immune Evasion

HSV employs several strategies to evade host immunity:

• ICP47 inhibits antigen presentation by blocking the transporter associated with antigen processing (TAP).
• gC and gE/gI interfere with complement and antibody-mediated immune responses.

2.5. Pathogenesis and Clinical Manifestations

• HSV-1: Causes oral herpes, herpetic keratitis (a leading cause of infectious blindness), and encephalitis.
• HSV-2: Causes genital herpes, neonatal herpes (via vertical transmission), and increases susceptibility to HIV acquisition.

3.Therapeutic Challenges in HSV Management

Current antiviral drugs are effective during active replication but do not eliminate latent virus. Resistance mutations, especially in thymidine kinase and DNA polymerase, reduce drug efficacy. Asymptomatic shedding and the lack of an effective vaccine further complicate management. Psychosocial factors and poor patient adherence are additional concerns.

3.1. Limitations of Existing Antiviral Drugs

The frontline treatment for HSV involves nucleoside analogs such as acyclovir, valacyclovir, and famciclovir. These drugs target the viral DNA polymerase, inhibiting replication during active infection.

3.2. Emergence of Drug Resistance

Antiviral resistance, particularly in immunocompromised individuals, poses a growing challenge. Resistance primarily arises from mutations in the thymidine kinase (TK) gene or viral DNA polymerase.

3.3. Latency and Viral Reactivation

Antiviral drugs do not reach effective concentrations in these ganglia nor do they affect latent viral DNA. Reactivation triggers include stress, immunosuppression, and UV exposure, leading to recurrent infections.

3.4. Asymptomatic Viral Shedding and Transmission

HSV can be transmitted even in the absence of visible lesions. This silent shedding complicates public health interventions and screening strategies. Many individuals are unaware of their infection status, contributing to continued transmission.

3.5. Psychosocial and Quality-of-Life Impact

HSV infections have a profound psychological and social burden. Recurrent outbreaks can affect self-esteem, sexual relationships, and mental health. The stigma associated with genital herpes often leads to non-disclosure and social withdrawal.

3.6. Limitations in Prophylactic and Therapeutic Vaccines

Despite decades of research, there is no FDA-approved HSV vaccine. Several candidates have failed in clinical trials. The virus’s immune evasion tactics complicate vaccine development.

3.7. Need for Novel Antiviral Strategies

There is a growing need for next-generation therapeutics, including latency-reversing agents, gene editing tools like CRISPR-Cas9, natural product-based antivirals, and combination therapies that can block replication, reactivation, and immune evasion.

4.0.Marine Microorganisms and Biosynthetic Diversity

Marine microbes produce a wide range of metabolites with antiviral activity. Their unique metabolic pathways are encoded by biosynthetic gene clusters such as PKS and NRPS. Marine actinomycetes, fungi, cyanobacteria, and algae generate structurally novel molecules with antiviral, antibacterial, and anticancer properties. Their potential against HSV is being actively investigated. These microbes produce structurally novel and biologically active secondary metabolites, many of which have no terrestrial analogs. Their biosynthetic diversity is driven by complex gene clusters, such as polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS), which generate compounds with potent antiviral, antibacterial, and anticancer properties. Because of this diversity, marine microbes are a rich source of bioactive molecules with promising potential in drug discovery, particularly against resistant and persistent pathogens like herpes simplex viruses (HSV).

5.0.Marine-Derived Anti-HSV Compounds

Examples include sulfated polysaccharides (e.g., carrageenan, fucoidan) from algae, peptides like A-3302-B from Micromonospora sp., and alkaloids such as manzamine A. These agents inhibit HSV at multiple stages: entry, replication, protein synthesis, and egress. Their low cytotoxicity and potential synergism with existing antivirals enhance their appeal. Sulfated polysaccharides like carrageenan and fucoidan from seaweeds inhibit viral attachment and entry. Manzamine A, an alkaloid from marine sponges, and peptides such as A-3302-B from Micromonospora species disrupt viral replication. Other marine-derived compounds including terpenoids, alkaloids, and phlorotannins target viral DNA polymerase or modulate host immunity. These compounds exhibit broad-spectrum activity, low cytotoxicity, and novel mechanisms, making them promising candidates for new antiviral drug development. Their potential to overcome resistance and target latent or recurrent infections highlights the marine biome’s therapeutic value against herpes simplex virus (HSV).

6.0.Preclinical Evidence and Models

In vitro studies using Vero and HeLa cells show anti-HSV activity of various marine compounds. Animal models (e.g., murine HSV skin and ocular models, guinea pig genital models) demonstrate efficacy in reducing lesion severity, viral titers, and inflammation. Some compounds like carrageenan have been tested in topical formulations for HSV-2. For antiviral research, cell lines infected with viruses help assess compound effectiveness, while animal models provide insights into pharmacokinetics and immune responses. Robust preclinical models are crucial for identifying promising bioactive compounds, optimizing dosing, and predicting potential toxicity, ultimately guiding the design of safe and effective clinical trials. This foundational step accelerates the development of novel therapeutics.

7.0. Synthetic Biology and Marine Drug Discovery

Synthetic biology tools like CRISPR and genome mining help identify and express biosynthetic gene clusters from uncultured marine microbes. These methods enable scalable production of promising antiviral compounds and the creation of novel analogs with improved properties. Many marine-derived drugs are challenging to harvest naturally due to low yields and ecological constraints. Synthetic biology overcomes these barriers by reconstructing biosynthetic gene clusters in heterologous hosts, enhancing compound production and modification. This approach accelerates the discovery and development of novel therapeutics by allowing scalable, sustainable, and tunable biosynthesis. Coupled with genome mining and metabolic engineering, synthetic biology expands access to marine natural products, supporting the development of new treatments for infectious diseases, including viral infections.

8.0. Challenges and Future Prospects

Challenges include difficulty in culturing marine microbes, low yields of compounds, regulatory issues, and high development costs. Future research should focus on deep-sea microorganisms, AI-assisted compound screening, and nanoparticle-based delivery systems to enhance solubility and bioavailability. Additionally, the cultivation of many marine microorganisms remains difficult, limiting the exploration of their full biosynthetic potential. Regulatory hurdles and high costs also slow the translation from discovery to clinical use. However, advancements in genomics, metagenomics, and synthetic biology are addressing these limitations by enabling genome mining, heterologous expression, and scalable production of marine natural products. Machine learning and AI further enhance the identification of promising leads. Looking ahead, interdisciplinary collaboration and innovative technologies will play a crucial role in overcoming current barriers. The integration of omics tools, bioinformatics, and biotechnological platforms holds promise for unlocking new marine-derived therapies, particularly for drug-resistant infections and viral diseases, making marine environments an increasingly vital resource in pharmaceutical development.

CONCLUSION

Marine microorganisms offer a rich, underexplored reservoir of antiviral agents with novel structures and mechanisms. They hold great promise for addressing therapeutic gaps in HSV management, particularly in drug-resistant and latent infections. Interdisciplinary approaches combining microbiology, pharmacology, and synthetic biology are key to translating marine bioactives into effective HSV therapies. These organisms produce structurally diverse metabolites with unique mechanisms of action, offering promising alternatives to existing antiviral agents and addressing the growing issue of drug resistance. Advances in isolation techniques, genome sequencing, and synthetic biology have revolutionized the discovery and development of marine-derived drugs, enabling researchers to explore previously inaccessible species and optimize the production of valuable compounds. Preclinical studies have demonstrated the efficacy of several marine natural products in inhibiting HSV replication and modulating host immune responses, laying the groundwork for future clinical applications. Despite existing challenges such as low natural yields, complex compound structures, and regulatory barriers innovative approaches like genome mining, metabolic engineering, and AI-driven drug discovery are helping to overcome these obstacles. Marine microorganisms offer a promising frontier for novel antiviral therapeutics. With continued interdisciplinary research and technological advancement, the potential of marine bioresources can be fully harnessed, contributing significantly to global health by delivering new, effective treatments against HSV and other viral infections. The future of marine drug discovery lies in sustainable innovation and collaborative exploration.

REFERENCES

1. Mayer AMS, Rodríguez AD, Taglialatela-Scafati O, Fusetani N. Marine pharmacology in 2014–2015: Marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action. Mar Drugs. 2019;17(2):97.
2. Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Marine natural products. Nat Prod Rep. 2021;38(2):362-413.
3.  Blunt JW, Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Marine natural products. Nat Prod Rep. 2018;35(1):8-53.
4. Martínez Andrade KA, Rangel-López E, García-Márquez LJ, González-Andrade M, Gómez-Cornelio S, Cuevas-González PF, et al. Marine natural products with antiviral activity against herpes simplex virus. Mar Drugs. 2022;20(3):193.
5.  Desriac F, Le Chevalier P, Brillet B, Leguerinel I, Thuillier B, Paillard C, et al. Exploring the antimicrobial potential of marine bacteria for drug discovery. Mar Drugs. 2019;17(10):512.
6.  Imran M, Salehi B, Sharifi-Rad J, Aslam Gondal T, Saeed M, Imran A, et al. Antiviral potential of marine algae and their sulfated polysaccharides: A comprehensive review. Mar Drugs. 2021;19(12):703.
7. Molinski TF, Dalisay DS, Lievens SL, Saludes JP. Drug development from marine natural products. Nat Rev Drug Discov. 2009;8(1):69-85.
8. Martins A, Vieira H, Gaspar H, Santos S. Marketed marine natural products in the pharmaceutical and cosmeceutical industries: Tips for success. Mar Drugs. 2014;12(2):1066-101.
9. Newman DJ, Cragg GM. Marine-sourced anti-infective agents: Recent developments. Mar Drugs. 2020;18(4):196.
10. Li YX, Himaya SWA, Kim SK. Triterpenoids of marine origin as anti-cancer agents. Molecules. 2013;18(7):7886-909.
11. Sun H, Gao R, Geng C, Xu Y, Fang W, Luo Y, et al. Antiviral activity of marine actinomycetes against herpes simplex virus. J Appl Microbiol. 2020;129(1):115-23.
12. Sagar S, Kaur M, Minneman KP. Antiviral lead compounds from marine sponges. Mar Drugs. 2010;8(10):2619-38.
13. Kim SK, Wijesekara I. Development and biological activities of marine-derived bioactive peptides: A review. J Funct Foods. 2010;2(1):1-9.
14. Jaspars M, Sun H, Chang L, Jian X, Ulanova D. Marine natural product drug discovery: Current status and future potential. J Mar Sci Eng. 2021;9(6):424.
15. Zainuddin EN, Aisaka K, Tachibana K, Miura M, Shinozaki T, Kobayashi J. Anti-HSV activity of batzelladines isolated from marine sponge Batzella sp. J Nat Prod. 2002;65(3):441-3.
16. Hu G, Yuan J, Sun J, Chen W, Xie H, Yang Q, et al. Advances in synthetic biology-based marine drug discovery. Mar Drugs. 2022;20(1):61.
17. Suleria HAR, Osborne S, Masci P, Gobe G. Marine-based nutraceuticals: An innovative trend in the food and supplement industries. Mar Drugs. 2017;15(10):272.
18. Song F, Ren B, Yu K, Chen C, Gu Y, Xu X, et al. Synthetic biology for the production of marine natural products: From discovery to industrialization. Mar Drugs. 2021;19(9):467.