Journal of Antivirals & Antiretrovirals
Open Access

Targeting Viral Replication: Advances in Polymerase and Protease Inhibitors

Sameera Jayasinghe^{* *}Correspondence: Sameera Jayasinghe, Department of Molecular Virology, Colombo Institute of Biomedical Research, Sri Lanka, Email:

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Description

Targeting key enzymes involved in viral replication, particularly polymerases and proteases, has proven to be a highly successful antiviral strategy across a variety of viral pathogens. These enzymes are essential for the replication cycle of viruses, and their inhibition leads to interruption of viral genome replication and maturation. In recent years, significant advancements in the development of polymerase and protease inhibitors have improved treatment outcomes for chronic viral infections such as HIV, hepatitis C (HCV), hepatitis B (HBV), and more recently, emerging viral threats including SARS-CoV-2. These developments have been driven by a better understanding of viral enzyme structures, the mechanisms of viral replication, and the development of high-throughput screening and structure-based drug design techniques.

Polymerase inhibitors target the viral RNA- or DNA-dependent polymerases responsible for genome replication. Nucleoside/ nucleotide analogues (NRTIs/NtRTIs) and non-nucleoside inhibitors (NNRTIs) form the backbone of HIV and HBV therapy. In HCV, sofosbuvir, a nucleotide analogue inhibitor of the NS5B RNA-dependent RNA polymerase, revolutionized treatment by achieving high sustained virologic response (SVR) rates with shorter therapy durations and fewer side effects. Similarly, remdesivir, an adenosine analogue, gained prominence during the COVID-19 pandemic for its inhibitory action against the RNA polymerase of SARS-CoV-2. Recent polymerase inhibitors are being designed to overcome issues of resistance, with a focus on high genetic barrier agents and pan-genotypic activity.

Protease inhibitors (PIs), on the other hand, interfere with the post-translational processing of viral polyproteins, a critical step in the production of functional viral proteins. In HIV treatment, protease inhibitors such as lopinavir, ritonavir, and darunavir significantly improved patient survival and disease management when used in combination with other drug classes. In HCV, the development of NS3/4A protease inhibitors—such as simeprevir, paritaprevir, and glecaprevir—marked another leap forward in achieving viral eradication. These drugs exhibit potent antiviral activity, with glecaprevir particularly noted for its pan-genotypic activity and use in combination with pibrentasvir.

The key to success in both classes lies in drug specificity and the ability to maintain activity against rapidly mutating viruses. Advances in crystallography and cryo-electron microscopy have allowed for detailed mapping of active sites in polymerases and proteases, enabling the development of inhibitors with higher binding affinities and reduced off-target effects. Additionally, drug developers are increasingly leveraging structure-activity relationship (SAR) data to enhance drug potency and pharmacokinetic properties.

However, a major challenge remains the emergence of drug resistance. Mutations in the active sites of polymerases and proteases can significantly reduce drug binding, rendering treatments less effective or even obsolete. To counter this, combination therapy—targeting multiple stages of the viral lifecycle—is often employed. This is evident in HAART for HIV and DAA regimens for HCV, where polymerase and protease inhibitors are used alongside other drug classes to achieve comprehensive viral suppression.

Another growing area is the exploration of viral polymerase and protease inhibitors for other pathogens such as cytomegalovirus (CMV), dengue virus, and Zika virus. Although currently lacking robust antiviral therapies, preclinical studies suggest that similar inhibition strategies could be adapted. Additionally, broad-spectrum antivirals that target conserved regions across multiple viruses are being investigated to prepare for future outbreaks and pandemics.

Formulation improvements are also playing a vital role in maximizing the effectiveness of these inhibitors. Long-acting formulations, including injectables and depot systems, are being developed to enhance patient adherence and reduce the risk of resistance. Furthermore, pharmacokinetic enhancers or boosters, such as cobicistat and ritonavir, are used to increase the bioavailability of protease inhibitors, enabling lower doses and better tolerability.

In conclusion, polymerase and protease inhibitors remain at the forefront of antiviral drug development, offering targeted mechanisms to disrupt viral replication with high efficacy. Their role has been instrumental in managing chronic viral infections and in responding rapidly to emerging threats. Continued research into resistance patterns, enzyme structure, and new delivery platforms will further strengthen the antiviral pipeline. As we confront evolving viruses and the constant risk of pandemics, the refinement and diversification of polymerase and protease inhibitors will be pivotal in ensuring preparedness and therapeutic success.