Papain

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Research Overview

Current research on papain spans three main application areas: (1) food and bioprocessing uses of papain as a protease for hydrolysis and tenderization, (2) physical/processing effects on papain activity and structure (e.g., ultrasound-induced conformational changes), and (3) biomedical research where “papain” appears primarily as a disease-modeling tool (notably papain-induced osteoarthritis in rodents) and as a namesake reference point for the SARS‑CoV‑2 papain-like protease (PLpro), a distinct viral enzyme targeted for antiviral drug discovery. In food systems, papain is frequently evaluated alongside other proteases (e.g., alcalase, bromelain) to generate protein hydrolysates from by-products (e.g., salmon frames) with defined yields, amino-acid profiles, peptide-size distributions, and functional properties such as antioxidant capacity; papain is also studied for its effects on muscle texture (e.g., squid tenderization) and associated quality attributes (e.g., water-holding capacity).

The strongest evidence supports papain’s effectiveness as a proteolytic processing aid: controlled enzymatic hydrolysis can produce high-protein hydrolysates with reproducible compositional characteristics, and papain-mediated proteolysis can measurably alter texture-related parameters in muscle foods (though sometimes with trade-offs such as reduced water-holding capacity). There is also solid mechanistic evidence that ultrasound can modulate papain activity by altering secondary/tertiary structure, supported by multiple spectroscopic readouts (circular dichroism, FTIR, fluorescence), indicating that papain performance is sensitive to processing conditions that perturb protein conformation. In contrast, biomedical findings in the studies reviewed here largely use papain as an inducer of osteoarthritis pathology (a model to test anti-inflammatory/chondroprotective agents such as sesamin or quercetin), rather than establishing papain itself as a therapeutic; separately, antiviral work focuses on SARS‑CoV‑2 PLpro inhibition using structural biology and in silico/in vitro screening, which is relevant to “papain-like” proteases but not directly to plant papain.

Key gaps include improved linkage between papain process parameters and end-use functionality in foods (e.g., mapping hydrolysis conditions to peptide profiles that drive antioxidant or other bioactivities, and mitigating quality drawbacks like moisture loss/WHC reduction during tenderization). More research is also needed on how industrially relevant physical treatments (ultrasound intensity/time, temperature, matrix composition) affect papain stability, kinetics, and reproducibility across real food matrices. Finally, clearer conceptual separation—and comparative enzymology—between plant papain and viral papain-like proteases would strengthen translational claims in the COVID-19 literature; while PLpro inhibitor discovery is advanced structurally, less-explored binding regions (e.g., alternative sites beyond dominant substrate-recognition pockets) and robust in vivo efficacy/PK validation remain important directions for future work.

1. What conditions has Papain been studied for?

  • Wound care (debridement of necrotic/devitalized tissue): Studied as an active enzyme incorporated into alginate-based wound dressings to provide proteolytic debridement activity and controlled release.

  • Osteoarthritis (OA) models: Papain is used to induce OA in rats via intra-articular injection (a disease model), then other compounds (e.g., sesamin, quercetin) are tested for therapeutic effects.

  • Intervertebral disc (IVD) degeneration models: Papain is used to induce disc degeneration in bovine organ culture (chemonucleolysis model) to mimic aspects of advanced degeneration.

  • Food processing / nutrition applications: Used to hydrolyze salmon frame proteins to produce protein hydrolysates with varying peptide size distributions and antioxidant capacity (positioned as nutritive supplements/ingredients).

  • Food texture modification: Used to tenderize jumbo squid muscle (enzymolysis), affecting texture parameters and water-holding capacity.

  • Enzyme stability/processing effects: Studied for how ultrasound alters papain activity via conformational (secondary/tertiary structure) changes.

  • Antimicrobial/biopreservation (exploratory): Proposed/assessed for antibacterial activity (including MIC/MBC approaches) in the context of Alicyclobacillus spp. spoilage; the study is truncated, so outcomes are not available here.

  • COVID-19 drug discovery (indirect relevance): Multiple studies focus on the SARS-CoV-2 papain-like protease (PLpro) as a drug target and inhibitors of PLpro. This is not papain supplementation; it concerns a viral enzyme that is “papain-like.”

2. Does it work in treating those conditions? Summarize the evidence.

  • Wound debridement (supportive, formulation-level evidence): An alginate dressing with immobilized papain retained substantial enzymatic activity after immobilization (~80% of initial activity) and showed improved stability over 28 days versus buffer (reported deactivation reduction on matrix vs buffer). It also released ~64.1% of enzyme over 24 hours in a Franz cell setup and showed in vitro biocompatibility testing in fibroblasts/keratinocytes consistent with a “bioactive material with proteolytic properties.” This supports feasibility for debridement-oriented dressings, but it is not a clinical outcomes trial.

  • Osteoarthritis (does not treat; it induces disease in models): In the OA rat studies, papain is the method used to create joint damage. The therapeutic effects reported are for sesamin and quercetin, not papain. Therefore, these studies do not support papain as an OA treatment; rather, they highlight papain’s capacity to cause cartilage pathology in experimental settings.

  • IVD degeneration (does not treat; it induces degeneration): In bovine IVD organ culture, papain (65 U/mL) produced pronounced degenerative changes (e.g., greatest glycosaminoglycan loss vs other enzymes, macroscopic voids, and height loss). This supports papain as a tool to model advanced degeneration, not as a therapy.

  • COVID-19 (no direct evidence for papain): The PLpro studies describe structural analyses and in silico/in vitro identification of PLpro inhibitors (including one study reporting micromolar inhibition and low cytotoxicity in a cell line). These findings do not test papain as a treatment and should not be interpreted as evidence that papain supplementation treats COVID-19.

3. What health benefits does it have?

  • Potential wound-care benefit via enzymatic debridement: Papain is described as capable of promoting debridement of devitalized/necrotic tissue, and an alginate-immobilized papain dressing maintained proteolytic activity with controlled release and improved stability in vitro—features consistent with a debriding dressing concept.

  • Indirect nutritional/functional-food relevance (as a processing aid): When used to hydrolyze salmon frame proteins, papain-generated hydrolysates were high in protein (~79–82%) and contained abundant amino acids; hydrolysates showed varying antioxidant capacities depending on conditions. This suggests papain can help generate protein ingredients that may have antioxidant activity, though the study frames this as a food supplement/ingredient rather than a direct clinical health benefit.

  • Food texture modification (non-health): Papain can tenderize tough muscle foods (e.g., squid), which may improve palatability, but this is a food-quality effect rather than a health outcome.

4. Does it have any downsides or side effects?

  • Tissue damage when injected/used to induce disease (preclinical models): Papain is explicitly used to induce osteoarthritis in rats and to induce disc degeneration in bovine IVDs. In the IVD model, papain caused macroscopic voids, the greatest glycosaminoglycan loss among enzymes tested, and measurable height loss—demonstrating strong matrix-degrading potential. This underscores that inappropriate exposure (especially direct tissue injection) can be harmful.

  • Potential adverse effects on food quality attributes: In squid tenderization experiments, papain (and bromelain) decreased water-holding capacity compared with controls, which can negatively affect juiciness/yield and may be undesirable in some food contexts.

  • Activity can be reduced by processing (ultrasound): Power ultrasound inhibited papain activity and altered secondary/tertiary structure (e.g., β-sheet changes; altered tryptophan fluorescence). This is not a “side effect” in humans, but it is a practical downside for manufacturing/handling because it can reduce enzyme effectiveness.

  • Clinical safety not established in these studies: The studies reviewed here do not report human adverse event rates, allergy risk, drug interactions, or dose-related side effects for oral papain supplements. Therefore, conclusions about typical supplement side effects cannot be made from this set of studies alone.

5. Is it beneficial or harmful for any genetic variations (pharmacogenomics)?

The studies reviewed here do not evaluate genetic variants (human or otherwise) that modify response to papain exposure or papain-based products. No pharmacogenomic markers, genotype-stratified outcomes, or variant-specific safety signals are described. Therefore, based on these studies, there is no evidence that papain is specifically beneficial or harmful for any particular genetic variation.

References

  1. Protein hydrolysate from salmon frames: Production, characteristics and antioxidative activity.
    Anthony Temitope Idowu, Soottawat Benjakul, Sittichoke Sinthusamran, Pornsatit Sookchoo, Hideki Kishimura (2019) - Journal of food biochemistry
  2. Effect of ultrasound on the activity and conformation of α-amylase, papain and pepsin.
    Zhi-Long Yu, Wei-Cai Zeng, Wen-Hua Zhang, Xue-Pin Liao, Bi Shi (2014) - Ultrasonics sonochemistry
  3. Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme.
    Ann Varghese, Jie Liu, Bailang Liu, Wenjing Guo, Fan Dong, Tucker A Patterson, Huixiao Hong (2025) - Molecules (Basel, Switzerland)
  4. Chondroprotective and anti-inflammatory effects of sesamin.
    Thanyaluck Phitak, Peraphan Pothacharoen, Jongkolnee Settakorn, Wilart Poompimol, Bruce Caterson, Prachya Kongtawelert (2012) - Phytochemistry
  5. Therapeutic effect and mechanism of action of quercetin in a rat model of osteoarthritis.
    Jun Zhang, Jing Yin, Daohong Zhao, Chaoran Wang, Yuhao Zhang, Yingsong Wang, Tao Li (2020) - The Journal of international medical research
  6. The mechanistic effect of bromelain and papain on tenderization in jumbo squid (Dosidicus gigas) muscle.
    Xu Jun-Hui, Cao Hui-Juan, Zhang Bin, Yao Hui (2020) - Food research international (Ottawa, Ont.)
  7. Molecular docking of potential SARS-CoV-2 papain-like protease inhibitors.
    Daoqun Li, Junwen Luan, Leiliang Zhang (2021) - Biochemical and biophysical research communications
  8. Targeting papain-like protease by natural products as novel therapeutic potential SARS-CoV-2.
    Muhammad Waqas, Saeed Ullah, Sobia Ahsan Halim, Najeeb Ur Rehman, Amjad Ali, Afnan Jan, Abdullatif Bin Muhsinah, Ajmal Khan, Ahmed Al-Harrasi (2024) - International journal of biological macromolecules
  9. Papain immobilized on alginate membrane for wound dressing application.
    Raimundo Nonato Fernandes Moreira Filho, Niédja Fittipaldi Vasconcelos, Fabia Karine Andrade, Morsyleide de Freitas Rosa, Rodrigo Silveira Vieira (2020) - Colloids and surfaces. B, Biointerfaces
  10. Chemonucleolysis combined with dynamic loading for inducing degeneration in bovine caudal intervertebral discs.
    Andrea Vernengo, Helen Bumann, Nadine Kluser, Astrid Soubrier, Amra Šećerović, Jan Gewiess, Jan Ulrich Jansen, Cornelia Neidlinger-Wilke, Hans-Joachim Wilke, Sibylle Grad (2023) - Frontiers in bioengineering and biotechnology
  11. Antibacterial activity of papain and bromelain on Alicyclobacillus spp.
    Márcia Maria dos Anjos, Angela Aparecida da Silva, Isabela Carolini de Pascoli, Jane Martha Graton Mikcha, Miguel Machinski, Rosane Marina Peralta, Benício Alves de Abreu Filho (2016) - International journal of food microbiology
  12. Papain and its inhibitor E-64 reduce camelid semen viscosity without impairing sperm function and improve post-thaw motility rates.
    C M Kershaw, G Evans, R Rodney, W M C Maxwell (2017) - Reproduction, fertility, and development
  13. Interaction between papain and transglutaminase enzymes on the textural softening of burgers.
    Wanessa Oliveira Ribeiro, Maristela Midori Ozaki, Mirian Dos Santos, Andrea Paola Rodríguez, Sérgio Bertelli Pflanzer, Marise Aparecida Rodrigues Pollonio (2021) - Meat science
  14. Increased physical activity severely induces osteoarthritic changes in knee joints with papain induced sulfate-glycosaminoglycan depleted cartilage.
    Michiel Siebelt, Harald C Groen, Stuart J Koelewijn, Erik de Blois, Marjan Sandker, Jan H Waarsing, Cristina Müller, Gerjo J V M van Osch, Marion de Jong, Harrie Weinans (2014) - Arthritis research & therapy
  15. Liposomes and transferosomes in the delivery of papain for the treatment of keloids and hypertrophic scars.
    Rachana Sapkota, Daniel J Munt, Anthony E Kincaid, Alekha K Dash (2023) - PloS one
  16. Scenedesmus obliquus: Antioxidant and antiviral activity of proteins hydrolyzed by three enzymes.
    Abd El-Moneim M R Afify, Gamal S El Baroty, Farouk K El Baz, Hanaa H Abd El Baky, Soha A Murad (2018) - Journal, genetic engineering & biotechnology
  17. Therapeutic effect of bromelain and papain on intestinal injury induced by indomethacin in male rats.
    Jameelah Y Madkhali, Rasha H Hussein, Hanan S Alnahdi (2023) - International journal of health sciences
  18. Structures of the free and inhibitors-bound forms of bromelain and ananain from Ananas comosus stem and in vitro study of their cytotoxicity.
    Mohamed Azarkan, Erik Maquoi, François Delbrassine, Raphael Herman, Nasiha M'Rabet, Rafaèle Calvo Esposito, Paulette Charlier, Frédéric Kerff (2020) - Scientific reports
  19. Papain Ameliorates Lipid Accumulation and Inflammation in High-Fat Diet-Induced Obesity Mice and 3T3-L1 Adipocytes via AMPK Activation.
    Yun-Mi Kang, Hyun-Ae Kang, Divina C Cominguez, Su-Hyun Kim, Hyo-Jin An (2021) - International journal of molecular sciences
  20. Effect of Er:YAG, Co2 lasers, papain, and bromelain enzymes dentin treatment on shear bond strength of composite resin.
    Farahnaz Sharafeddin, Sara Maroufi (2022) - Clinical and experimental dental research


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This article summarizes published research for educational purposes. It is not medical advice. Talk to your doctor before starting, stopping, or changing any supplement or medication.

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