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Review
. 2025 Aug 21:16:1621590.
doi: 10.3389/fphar.2025.1621590. eCollection 2025.

Broad-spectrum therapeutic potential of 4-phenylbutyrate in neurological and systemic diseases of viral and non-viral origin

Fatima Bobat #  1 , David Wu #  1 , Ethan Tu  1   2 , Divya Kapoor  1   3 , Pankaj Sharma  1 , Joseph S Adams  4 , Chima Orameh  1 , Tejabhiram Yadavalli  1 , Abhijit Date  4 , Deepak Shukla  1   3
Affiliations
Review

Broad-spectrum therapeutic potential of 4-phenylbutyrate in neurological and systemic diseases of viral and non-viral origin

Fatima Bobat et al. Front Pharmacol. .

Abstract

4-Phenylbutyrate (4-PBA), initially recognized for treating urea cycle disorders, has emerged as a potent therapeutic agent with broad-spectrum potential. As a chemical chaperone, 4-PBA modulates protein folding and reduces endoplasmic reticulum stress. 4-PBA has demonstrated efficacy in treating ocular herpes simplex virus type 1 (HSV-1) infection and HSV-1-induced encephalitis, highlighting its potential as a novel anti-herpetic therapy. Beyond its antiviral properties, 4-PBA's therapeutic reach extends to neurological disorders linked to HSV-1 infection, including Parkinson's, Alzheimer's, Huntington's diseases, and primary open-angle glaucoma. Furthermore, 4-PBA shows promise in treating a diverse array of conditions beyond neurology. Its potential has been explored in atherosclerosis, Adriamycin-induced cardiac injury, non-alcoholic fatty liver disease, rifamycin-induced liver injury, chronic kidney disease, diabetic nephropathy, NSAID-induced kidney injury, and chronic wound healing. This review synthesizes the multifaceted therapeutic potential of 4-PBA, emphasizing its role as a broad-spectrum agent capable of addressing a wide range of pathological conditions, particularly its role in combating HSV-1 and associated neurological disorders. The growing evidence suggests that 4-PBA may be a versatile and valuable addition to the therapeutic arsenal against multiple diseases.

Keywords: 4-phenylbutyrate (4-PBA); Broadspectrum; herpes simplex virus; neurological disorders; therapeutic.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Chemical structure of butyric acid, 4-phenylbutyric acid (PBA), and PBA prodrugs.
FIGURE 2
FIGURE 2
PBA synthesis methods 1) Jobdevairakkam and Muthiah (2007) US 2007/0004805 A1 2) Burzynski and Musial (2002) US 6,372,938 B1.
FIGURE 3
FIGURE 3
Urea cycle disorder - reproduced from (Lee and Kim, 2022).
FIGURE 4
FIGURE 4
Conversion scheme of phenylbutyrate (PBA) to phenylacetate (PAA).
FIGURE 5
FIGURE 5
Mechanism showing potential anti-inflammatory activity of 4-PBA (Created in bioRender).
FIGURE 6
FIGURE 6
Known mechanisms of action of 4-PBA (Created in bioRender).
FIGURE 7
FIGURE 7
Representation of organs targeted by 4-PBA (created in bioRender).
See this image and copyright information in PMC

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