Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Shikimic acid (CAS No. 138-59-0) serves as a key metabolic intermediate in the biosynthesis pathway of aromatic amino acids, and is widely found in plants, microorganisms, and certain fungi. Its unique chemical structure and biological activity have attracted significant attention in the field of natural product pharmacology. Shikimic acid is not only a precursor to various aromatic compounds but also an important starting material for antiviral drug synthesis, playing a key role in the production of the anti-influenza drug oseltamivir (Tamiflu). In recent years, with in-depth research into its pharmacological activity and molecular mechanisms, shikimic acid has shown broad application potential in antiviral, anti-inflammatory, and immunomodulatory areas. This paper will systematically review the chemical structure and physicochemical properties of shikimic acid, plant origin and extraction methods, pharmacological activity studies, mechanisms of action and molecular targets, druggability evaluation, and pharmacokinetics, and finally explore its clinical application prospects and future development directions.

Chemical structure and physicochemical properties

Shikimic acid has the chemical name 3,4,5-trihydroxycyclohex-1-ene-1-carboxylic acid, molecular formula C7H10O5, and molecular weight 174.1520. Its structural feature is a cyclohexene ring, with hydroxyl groups replacing the 3, 4, and 5 positions, and it possesses a specific stereochemical configuration (3R, 4S, 5R), giving it high stereoselectivity. As a cyclohexene carboxylic acid, shikimic acid possesses both hydroxy monocarboxylic acids and α,β-unsaturated monocarboxylic acids, demonstrating good water solubility (109.5634 mg/mL) with a LogP value of -1.4628, indicating strong hydrophilicity, difficulty in free diffusion through lipid membranes, and low blood-brain barrier permeability.

The polar surface area (TPSA) of shikimic acid is 97.99 Ų, indicating strong polarity and hydrogen bond donor/acceptor capability, which is significant for binding to biological macromolecule targets. It has good chemical stability and does not exhibit hERG channel inhibition. Ames-induced mutagenic test results were negative, indicating high safety and promising drug potential.

Plant Origins and Extraction Methods

Shikimic acid is widely found in various plants and microorganisms, with Illicium verum fruit being especially abundant, serving as the main source of industrial extraction. In addition, certain strains such as Saccharomyces cerevisiae and E. coli can also synthesize shikimic acid, making them important subjects for biosynthesis research.

Traditional extraction methods mainly rely on extracting plant materials with water or alcohol solvents, combined with acid-base adjustment and crystallization purification processes. In recent years, the application of ultrasound-assisted extraction, microwave-assisted extraction, and membrane separation technologies has significantly improved extraction efficiency and purity. Biological fermentation uses genetic engineering to modify microbial strains and achieve efficient production of shikimic acid, becoming an important alternative to traditional plant extraction.

Pharmacological activity research

The pharmacological activity of shikimic acid is mainly concentrated in the antiviral field, covering inhibitory effects on various viral targets. Research shows that shikimic acid and its derivatives have significant inhibitory effects against viruses such as influenza, herpes, and HIV. Its antiviral activity involves multiple interventions in viral replication, transcription, and viral protein function.

In addition, shikimic acid exhibits certain anti-inflammatory activity, which can regulate immune cell function and inhibit the release of inflammatory factors. Some studies indicate that shikimic acid also has potential in antioxidant and neuroprotective aspects. Although its blood-brain barrier permeability is relatively low, it is expected to achieve central nervous system efficacy through structural modification or carrier systems.

Mechanism of action and molecular targets

The antiviral mechanism of shikimic acid involves multiple virus-related targets, including myeloperoxidase (MPO), herpesvirus gene products UL42, UL54, ICP27, TK (thymidine kinase), viral envelope glycoprotein gD, as well as HIV-related CCR5, CXCR4 receptors, HIV1 protease (HIV1-PR), and integrase (INT).

Shikimic acid interferes with viral replication cycles and infection processes by binding to these targets. For example, shikimic acid can inhibit the functions of UL42 and UL54 proteins, blocking the replication of herpes virus DNA; Regulation of HIV's CCR5 and CXCR4 receptors, reducing the virus's ability to enter host cells; It simultaneously inhibits HIV1-PR and integrase activity, blocking viral protein maturation and genomic integration.

Additionally, shikimic acid regulates the host's immune response, enhances antiviral immunity, and exerts indirect antiviral effects. These multi-target and multi-mechanism characteristics make shikimic acid an ideal candidate for antiviral drug development.

Druggability evaluation and pharmacokinetics

Shikimic acid has a moderate molecular weight, high polarity, and good water solubility, meeting the physicochemical requirements of most oral drugs. Its negative LogP value indicates strong hydrophilicity and poor lipid solubility, limiting its passive diffusion ability through cell membranes. The low permeability of the blood-brain barrier suggests that its application in central nervous system diseases requires drug delivery systems or structural optimization.

In terms of safety, shikimic acid does not inhibit hERG channels, reducing the risk of cardiotoxicity; A negative Ames test indicates no mutagenicity and a solid safety foundation.

Pharmacokinetic studies show that shikimic acid is absorbed rapidly in the body, but its bioavailability is limited by its polarity and metabolic stability. Through methods such as nanocarriers, liposome encapsulation, and chemical modification, its distribution and stability in vivo can be improved, enhancing its efficacy.

Prospects and outlooks for clinical applications

Shikimic acid, as a molecule with significant antiviral activity in natural products, has broad clinical application prospects. As a key precursor to anti-influenza drugs such as oseltamivir, it has played an important role in the pharmaceutical industry. In the future, shikimic acid and its derivatives are expected to be developed as broad-spectrum antiviral drugs targeting various viral infections, especially showing potential in the prevention and control of emerging and resistant virus strains.

Moreover, shikimic acid's immunomodulatory and anti-inflammatory activities offer new ideas for its application in autoimmune and inflammatory diseases. By combining modern drug delivery technologies and structural optimization strategies, shikimic acid is expected to break through the blood-brain barrier limits and expand into the treatment of neurological diseases.

Future research should focus on elucidating the mechanism of shikimic acid, optimizing pharmacokinetics, and evaluating preclinical safety to promote its clinical translation. At the same time, advances in biosynthesis technology will promote the sustainable production of shikimic acid, reduce costs, and enhance industrialization levels.

Conclusion

As a key intermediate in the biosynthesis pathway of aromatic amino acids, shikimic acid has become an important subject of natural product pharmacological research due to its unique chemical structure and multi-target antiviral activity. Its excellent physicochemical properties and safety lay the foundation for druggability, and its abundant plant and microbial sources ensure its supply. With deeper understanding of its pharmacological mechanisms and optimization of pharmacokinetics, shikimic acid has increasingly broad application prospects in antiviral and immunomodulatory fields. In the future, combined with modern drug development technologies, shikimic acid is expected to become an important representative of the new generation of natural products, providing strong support for human antiviral therapy.