key: cord-0780989-hlhys3rb
authors: Dilokthornsakul, Witoo; Kosiyaporn, Ramanya; Wuttipongwaragon, Rattanamanee; Dilokthornsakul, Piyameth
title: Potential effects of propolis and honey in COVID-19 prevention and treatment: A systematic review of in silico and clinical studies
date: 2022-01-31
journal: J Integr Med
DOI: 10.1016/j.joim.2022.01.008
sha: 334ebbf2897129f498e5e8b3f4f59af8c90d0ad2
doc_id: 780989
cord_uid: hlhys3rb

BACKGROUND: Propolis and honey have been studied as alternative treatments for patients with coronavirus disease 2019 (COVID-19). However, no study has yet summarized the full body of evidence for the use of propolis and honey in COVID-19 prevention and treatment. OBJECTIVE: This study systematically reviews the mechanisms of propolis and honey against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and current evidence for the use of propolis and honey in COVID-19 prevention and treatment. Search strategy: A systematic search was conducted of electronic databases including PubMed, Scopus, ScienceDirect, and Cochrane Library from their inceptions to April 2021. Inclusion criteria: Studies that evaluated the effect of propolis or bee products against SARS-CoV-2 using in silico methods, clinical studies, case reports and case series were included. Data extraction and analysis: A standardized data extraction form was used, and data were extracted by two independent reviewers. Narrative synthesis was used to summarize study results concerning the use of propolis or honey in COVID-19 prevention and treatment and their potential mechanisms of action against SARS-CoV-2. RESULTS: A total of 15 studies were included. Nine studies were in silico studies, two studies were case reports, one study was a case series, and three studies were randomized controlled trials (RCTs). In silico studies, using molecular docking methods, showed that compounds in propolis could interact with several target proteins of SARS-CoV-2, including angiotensin-converting enzyme 2, the main protease enzyme, RNA-dependent RNA polymerase, and spike protein. Propolis may have a positive effect for clinical improvement in mild and moderate-to-severe COVID-19 patients, according to case reports and case series. The included RCTs indicated that propolis or honey could probably improve clinical symptoms and decrease viral clearance time when they were used as adjuvant therapy to standard of care. CONCLUSION: In silico studies showed that compounds from propolis could interact with target proteins of SARS-CoV-2, interfering with viral entry and viral RNA replication, while clinical studies revealed that propolis and honey could probably improve clinical COVID-19 symptoms and decrease viral clearance time. However, clinical evidence is limited by the small number of studies and their small sample sizes. Future clinical studies are warranted. Please cite this article as: Dilokthornsakul W, Kosiyaporn R, Wuttipongwaragon R, Dilokthornsakul P. Potential effects of propolis and honey in COVID-19 prevention and treatment: A systematic review of in silico and clinical studies. J Integr Med. 2022; Epub ahead of print.

The coronavirus disease 2019 (COVID-19) pandemic has affected people worldwide [1] . As of April 2021, approximately more than 200 million people were infected, resulting in over 4.9 million deaths [2] , and the number of infections continues to rise. The numbers of infected patients have been increasing. Most COVID-19 patients develop mild to moderate respiratory symptoms, including dry cough, shortness of breath and sore throat. However, serious acute respiratory distress syndrome also develops in some patients, especially in the elderly or those with chronic diseases.

Health interventions have been implemented to reduce the rate of COVID-19 infection, including face masks, physical distancing, hand hygiene, and vaccines [3] . Medications have also been used to treat COVID-19-infected patients, such as antimalarial agents, antiviral therapy, immunebased therapy, and corticosteroids [4, 5] . Herbal medicine is a class of natural substances and are also used as adjuvant therapies for COVID-19. Some natural substances are reported to have inhibitory effects on coronavirus, such as psoralidin, silvestrol, quercetin, myricetin, flavonoids, and polyphenols [68].

Propolis, a resinous bee product, has been reported to have antimicrobial activities, based on its content of phenolic compounds, flavonoids, and esters of aromatic acids [911] . Specific to antiviral activities, propolis has been shown to inhibit varicella-zoster virus, herpes virus, and human immunodeficiency virus [1214] . For COVID-19, pre-clinical studies report the interaction of propolis and some target proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 [15, 16] . In addition, some clinical studies have shown a potential positive effect of propolis and honey products on SARS-CoV-2 viral clearance and patients' symptoms [17, 18] . However, no study has yet summarized all of the available evidence concerning the use of propolis or honey for COVID-19 prevention and treatment.

This study systematically reviewed possible mechanisms of propolis and honey against SARS-CoV-2, and clinical evidence relevant to the effect of propolis and honey for COVID -19 prevention and treatment. This synthesis will be useful for supporting clinical decision making and the development of propolis and honey products for COVID-19 management.

We systematically searched relevant studies from PubMed, Scopus, ScienceDirect, and Cochrane Library from their inceptions to April 2021. We also performed citation tracking from related articles to identify additional studies. Search terms were ("SARS-CoV-2" OR "severe acute respiratory syndrome coronavirus 2" OR "COVID-19" OR "coronavirus" OR "coronavirus disease" OR "novel coronavirus" OR "2019-nCoV" OR "COVID-2019 pneumonia") AND ("propolis" OR "bee glue" OR "bee product" OR "honey"). Details of the search strategies used in each database are reported in Supplementary file Table S1.

Studies that met the following criteria were included: (1) studies on the effect of propolis and bee products against SARS-CoV-2, and (2) reports fitting the classifications of in silico studies, clinical studies, case report and case series. Studies reported in abstract form only and incomplete studies were excluded. Resources identified in the search were de-duplicated using EndNote TM version 20 (Clarivate Co. Ltd). All identified articles were independently reviewed by two authors (RW and RK). All disagreements were resolved through discussion with a third reviewer (WD).

A standardized data extraction form was developed for this study. The extracted data included authors, year of publication, country, study design, intervention, comparator, inclusion and exclusion criteria, number of participants, methods, duration of assessment, and outcomes. For in silico studies, binding affinity was the primary outcome, while clinical symptom improvement was the primary outcome for clinical studies. Data extraction was performed by RW and RK and validated by WD and PD.

The quality of studies was assessed by RW and RK. Indicators of evidence quality and scoring system [1921] were used to assess the quality of in silico studies. The JBI Critical Appraisal Checklist was used for case reports [22] , the National Institutes of Health Quality Assessment Tool was used for case series [23], while version 2 of the Cochrane risk-of-bias tool was used to assess the quality of randomized controlled trials (RCTs) [24] .

Various compounds from propolis and honey were reported to have activity against SARS-CoV-2. Study design, intervention, and outcomes of interest were also different. Therefore, metaanalysis could not be performed. Narrative synthesis was used to summarize evidence on the use of propolis and honey for COVID-19 prevention and treatment. It was also used to summarize the potential mechanisms of these products against SARS-CoV-2.

A total of 423 studies were retrieved from the database searches. Fifteen studies were included in this systematic review (Fig. 1) . Nine studies were in silico studies [7,8,16,2530] , while three studies were case reports or case series [18, 31, 32] , and the other three studies were RCTs [17, 33, 34] . Of the nine in silico studies, two studies determined the effect of propolis against SARS-CoV-2 angiotensin-converting enzyme 2 (ACE2) [7, 8] , six studies used SARS-CoV-2 main protease enzyme as the target enzyme [16,2529] , two studies used SARS-CoV-2 RNAdependent RNA polymerase as the target enzyme [16, 29] , three studies focused on spike protein subunit one [16, 27, 30] , and one study focused on spike protein subunit two [25] . The molecular docking method was used to determine the binding affinity of propolis on the target protein. Of the clinical studies, two were case reports [31, 32] , while one was a case series [18] . The case reports followed the use of commercial propolis for COVID-19 treatment. One case was a patient with mild COVID-19 symptoms, while the other case was a patient with severe COVID-6 / 29 19 symptoms. The case series study reported a total of 40 subjects . Twenty subjects used   propolis for COVID-19 prevention, while the rest used propolis for COVID-19 treatment. Three RCTs [17, 33, 34] reported the effect of propolis or honey, as an adjuvant to standard care, on clinical symptoms of COVID-19. One study reported the effect of honey with Nigella sativa seeds on time of clinical symptom improvement and time to viral clearance [17] . One study reported the effect of propolis plus Hyoscyamus niger extract on clinical symptom scores [33] .

Another study reported the effect of Brazilian green propolis extract on length of hospital stay, oxygen therapy dependency time, the number of acute kidney injuries, the use of renal replacement therapy, invasive ventilation, vasoactive agents, and intensive care unit (ICU) stay [34] .

Five in silico studies were assessed as having no discernable bias [16,2628,30] . One study was assessed as having weak bias because the study did not report the reason for choosing the compounds [8] . Three studies were assessed as having moderate bias because of the discrepancy between their abstracts and study results. Another reason was because the study did not report the reason for choosing the compounds [7, 25, 29] (Supplementary file Table S2 ).

One case report was assessed as a good-quality study [32] . The study clearly described the patient's demographic characteristics, diagnostic tests, assessment methods, and the treatment outcomes. Another case report was assessed as being of fair quality [31] . The study did not sufficiently provide patient's history and clear takeaway lessons (Supplementary file Table S3 ).

One case series [18] was assessed as a fair-quality study. The study did not clearly describe the study population, and participants were not comparable because they received different interventions (Supplementary file Table S4 ).

All included RCTs [17, 33, 34] were assessed as having high risk of bias. This was because of the lack of a clear randomization process, questionable outcome measures, or the selection of reported results (Supplementary file Table S5 ).

SARS-CoV-2 ACE2 was used as the target enzyme in two studies [7, 8] . One study [7] showed that 12 compounds from propolis had positive binding affinity to SARS-CoV-2 ACE2. It also indicated that rutin had the highest binding affinity with 8.04 kcal/mol, which was higher than its positive control (7.24 kcal/mol). Another study found that 13 compounds from propolis had positive binding affinity to SARS-CoV-2 ACE2. Glyasperin A was reported to have the highest binding affinity to SARS-CoV-2 ACE2 (10.8 kcal/mol) which was higher than its positive control (9.2 kcal/mol) [8] (Table 1 and Table 2 ). 

A total of six in silico studies were conducted using the SARS-CoV-2 main protease enzyme as the target enzyme [16,2529] . Several compounds from propolis had high binding affinity to the SARS-CoV-2 main protease enzyme, including octacosane (7.39 kcal/mol) [16] , 3′methoxydaidzin (7.7 kcal/mol) [25], sulabiroins A (8.1 kcal/mol) [26] , rutin (92.8 kcal/mol) [27] , glyasperin A (7.8 kcal/mol) [28] , broussoflavonol F (7.8 kcal/mol) [28] , and kaempferol (7.8 kcal/mol) [29] ( Sulabiroins A had the highest binding affinity compared to the other 19 compounds, which was lower than native ligand (N3).

Elwakil et al. [16] Lopinavir: -8.18

Acid: n-hexadecanoic acid (-6.28), benzoic acid (-3.70), trans-caffeic acid (-4.48), tetradecanoic acid (-5.84), and trans-13octadecenoic acid (-6.06)

Octacosanol showed the highest binding affinity compared to the other 25 compounds, which was lower than lopinavir. Rutin had the highest binding affinity compared to the other 9 compounds, which was higher than favipiravir and hydroxychloroquine. However, it was lower than native ligand (N3) and remdesivir for the SARS-CoV-2 main protease. Sahlan et al. [28] 13b: -8.2

New podophyllotoxin derivative: sulabiroins A (-7.6) Glyasperin A and broussoflavonol F had the highest binding affinity compared to the other 19 compounds, but they were lower than 13b for the SARS-CoV-2 main protease. Shaldam et al. [29] Not available 2,2-Dimethyl-8-prenylchromene (-6.8) Kaempferol had the highest binding affinity compared to 13 other compounds.

Phenylpropanes: artepillin C (-7.5), 3-prenyl cinnamic acid allyl ester (-6.2), isocupressic acid (-6.4), 13C-symphyoreticulic acid (-6.9), ellagic acid (-7.5), syringic acid (-5.6), caffeic acid phenethyl ester (-7.0), p-coumaric acid (-5.6), hesperetin (-7.4), naringenin (-6.5), kaempferol (-7.8), quercetin (-7.4), and chrysin (-7.2) RNA-dependent RNA polymerase Elwakil et al. [16] Remdesivir: -6.77

Acid: n-hexadecanoic acid (-5.70), benzoic acid (-3.91), trans-caffeic acid (-4.80), tetradecanoic acid (-5.34), and trans-13octadecenoic acid (-5.97)

Octatriacontyl pentafluoropropionate had the highest binding affinity compared to the other 24 compounds, which was higher than the reference drug, remdesivir. 

SARS-CoV-2 RNA-dependent RNA polymerase was used as the target enzyme in two studies [16, 29] . One study reported that octatriacontyl pentafluoropropionate had the highest binding affinity to SARS-CoV-2 RNA-dependent RNA polymerase (8.20 kcal/mol), which was higher than remdesivir (6.77 kcal/mol) [16] . Another study indicated that ellagic acid (6.4 kcal/mol) had the highest binding affinity to SARS-CoV-2 RNA-dependent RNA polymerase [29] ( Table   2 ).

Three studies used SARS-CoV-2 spike protein subunit 1 [16, 27, 30] , while one study used SARS-CoV-2 spike protein subunit 2 as their target proteins [25] . Several compounds showed positive binding affinity to SARS-CoV-2 spike protein subunit 1. Octatriacontyl pentafluoropropionate had the highest binding affinity in one study [16] , while rutin (94.3 kcal/mol) had the highest binding affinity in another study [27] . Another study showed the positive binding affinities of chrysin (8.1 kcal/mol) and galangin (8.2 kcal/mol) [30] to SARS-CoV-2 spike protein subunit 1 ( Table 2) .

Two case reports and one case series were identified in our literature search [18, 31, 32] . The case of a 52-year-old female patient with mild COVID-19 was reported in Brazil [31] . A 30%

propolis solution was used as her main treatment, along with a healthy diet and adequate hydration. Forty-five drops, three times a day of the product were administered for 14 d. The patient was clinically improved after 12 d of treatment. In addition, the patient had a negative reverse transcription polymerase chain reaction (RT-PCR) test result for SARS-CoV-2 after 12 d of treatment (Table 3 and Table 4 ).

The case of a 38-year-old male patient with severe COVID-19 was reported in Turkey [32] . A 30% propolis solution was used as his adjuvant therapy along with hydroxychloroquine, favipiravir and tocilizumab. Twenty drops of the propolis solution were administered per day initially, with the dose increasing to 80 drops per day. The patient's clinical symptoms were improved after seven days of treatment, and the patient was discharged on day 10 (Table 3 and   Table 4 ).

A retrospective case series study was reported in Egypt [18] . In this report, 20 within five to ten days, and one patient (5.0%) improved after more than ten days. In the end, all patients showed clinical improvement and had negative nasopharyngeal swab PCR tests (Table 3 and Table 4 ). No patient had propolis treatment discontinued due to side effects. The percentages of patients experiencing adverse events were not different significantly among the three groups. The most severe adverse event overall was shock/need for vasoactive drugs and acute respiratory failure.

CRP: C-reactive protein; ICU: intensive care unit; IQR: inter-quartile range; NR: not reported; RT-PCR: real-time polymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SD: standard deviation.

A total of three RCTs were identified in the literature search [17, 33, 34] . All studies used propolis or honey as an adjuvant therapy along with standard of care, such as antipyretics, corticosteroids, or supplemental oxygen.

A double-blinded RCT was conducted [17] to assess the effect of honey on COVID-19 symptoms. A total of 313 hospitalized patients received 1 g of honey plus 80 mg/(kg·d) of Nigella sativa seed with standard of care or standard of care with placebo. The study showed that patients with moderate symptoms receiving honey had a lower median time to alleviation of symptoms than patients with standard of care plus placebo (4 vs 7 d, P < 0.001). Similarly, the time to alleviation of symptoms was shorter in patients with severe cases who received honey than in those who received placebo (6 vs 13 d, P < 0.001). Patients receiving honey also had a lower median time to viral clearance than patients with placebo (P < 0.001 for both moderate and severe patients). In addition, patients who received honey products had improved clinical symptoms compared to those receiving placebo (Table 3 and Table 4 ).

An RCT was conducted to determine the efficacy of propolis in combination with H. niger extract, compared to the standard of care in COVID-19 patients visiting outpatient clinics [33] . Fifty COVID- niger extract had lower scores for some clinical symptoms, including dry cough (P < 0.01), shortness of breath (P < 0.01), sore throat (P < 0.01), and chest pain (P < 0.05), at day six. No significant differences were observed for other clinical symptom scores (Table 3 and Table 4 ). (Table 3 and Table 4 ).

Only four clinical studies reported safety outcomes [17, 18, 33, 34] . One study reported no adverse events related to propolis or honey [17] , while three studies reported some adverse events related to propolis or honey. One study [18] reported non-serious adverse events from three patients. The adverse events were sweating, hyperglycemia, and diarrhea. The second study reported one patient experienced hot flashes [33] , and the third reported no significant difference in adverse events between patients receiving propolis and standard of care [34] .

This One possible mechanism of propolis against SARS-CoV-2 infection is to interfere with viral entry, an essential process for viral infection [35] . In silico studies [7, 8, 16, 25, 27, 30] showed higher binding affinity of some active compounds of propolis to spike proteins or human ACE2 than positive controls.

SARS-CoV-2 invades host cells by engaging its spike protein S1 subunit with human ACE2. It also uses the spike protein S2 subunit to bind the virus to the host cell membrane [36, 37] . The interaction between propolis and human ACE2 or viral spike protein S1 and S2 could disrupt the viral entry process.

Another possible mechanism is to interfere with the viral replication process. SARS-CoV-2 uses the main protease to cleave the viral genome polyproteins, pp1a and pp1ab, into functional proteins which initiate viral replication by forming a replication complex with RNA-dependent RNA polymerase.

Establishing the replication complex is crucial for the viral replication process [3739] . Some studies revealed interactions between some chemical constituents of propolis and the SARS-CoV-2 main protease [16,2529] ; some studies also showed that compounds present in propolis could inhibit RNAdependent RNA polymerase activity [16, 29] . These interactions between propolis and SARS-CoV-2

proteins inhibit viral replication. Propolis contains compounds that interact with SARS-CoV-2 through several possible mechanisms, which might synergistically increase its antiviral activities.

Clinical studies have indicated the positive effect of propolis and honey for improvement of some clinical symptoms such as dry cough, sore throat, and fever in patients with both mild and moderate to severe symptoms. These benefits were due to propolis's ability to hasten viral clearance, as observed in in silico studies. In addition, the clinical improvement might be due to other therapeutic activities of propolis. Some active compounds in propolis and honey have anti-inflammatory activities [40, 41] .

Galangin, one of the active compounds in propolis, has been shown to inhibit tumor necrosis factor-α and interleukin-8, leading to a decrease in tissue inflammation and clinical symptoms. The clinical studies summarized here did not report which viral types were studied. Based on the time of the study conducted, the viral type could have been the wild type. The effect of propolis or honey could be different for other variants, because SARS-CoV-2 mutates its spike protein, which is one of the possible target proteins for propolis. The observed clinical effect might be different for other variants of concern, including α, β, γ, or δ variants.

Although we comprehensively searched through several databases, only three RCTs were identified. In addition, the RCTs were conducted on different populations, using different interventions and different outcome measures. Therefore, meta-analysis could not be performed. Moreover, all studies were assessed as having a high risk of bias, because they incompletely reported some important methodology and measured many clinical parameters, leading to the possibility of biases. These limitations suggest that readers should interpret the clinical findings with caution.

This review signifies a potential effect of propolis and honey on COVID-19 as an adjuvant treatment.

In silico studies showed that compounds present in propolis can interact with target proteins of SARS-CoV-2, potentially interfering with viral entry or viral RNA replication. Clinical studies revealed that propolis or honey could probably improve clinical COVID-19 symptoms and decrease viral clearance time. However, clinical evidence of the effect, appropriate dose, and suitable dosage forms are limited by the small number of studies and small sample sizes. Future investigations should be undertaken to strengthen the understanding of potential benefits from honey and propolis.

This study has no funding support.

All authors designed the study's hypothesis and protocol. RK and RW were responsible for data collection. All authors participated in data analysis. All authors also participated in data interpretation, manuscript preparation and review, table and figure preparation, and the scientific discussion of the data. All authors approved the final version of this manuscript.

All authors declare no conflict of interest related to this study. Table S5 . Quality assessment using version 2 of the Cochrane risk-of-bias tool for randomized controlled trials. Item Study

5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino}-4-methylpentanoic acid; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

Timeline: WHO's COVID-19 response

COVID-19: a review of the effectiveness of non-pharmacological interventions

Chloroquine and hydroxychloroquine for the prevention and treatment of COVID-19: a fiction, hope or hype? An updated review

Investigation of potential inhibitor properties of ethanolic propolis extracts against ACE-II receptors for COVID-19 treatment by molecular docking study

Evaluating the potency of Sulawesi propolis compounds as ACE-2 inhibitors through molecular docking for COVID-19 drug discovery preliminary study

Back to the basics: propolis and COVID-19

The role of honey and propolis in the treatment of infected wounds

Propolis: chemical composition, biological properties and therapeutic activity

Mechanism of herpes simplex virus type 2

Anti-AIDS agents

Anti-HIV activity of moronic acid derivatives and the new melliferone-related triterpenoid isolated from Brazilian propolis

A comparative multi-centre study of the efficacy of propolis, acyclovir and placebo in the treatment of genital herpes (HSV)

Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: running title: propolis against SARS-CoV-2 infection and COVID-19

Potential anti-COVID-19 activity of Egyptian propolis using computational modeling

Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): a multi-center placebo-controlled randomized clinical trial

Promising preventive and therapeutic effects of TaibUVID nutritional supplements for COVID-19 pandemic: towards better public prophylaxis and treatment (a retrospective study)

Building confidence in geological models

Better environmental decision making-recent progress and future trends

A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data

National Heart, Lung, and Blood Institute. Quality assessment tools for case series studies

In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

Identifying propolis compounds potential to be COVID-19 therapies by targeting SARS-CoV-2 main protease

Optimization and evaluation of

Molecular interaction analysis of Sulawesi propolis compounds with SARS-CoV-2 main protease as preliminary study for COVID-19 drug discovery

In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes

In silico evaluation of flavonoids as effective antiviral agents on the spike glycoprotein of SARS-CoV-2

Antiviral activity of Brazilian green propolis extract against SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection: case report and review

COVID-19 and anatolian propolis: a case report

The effect of to COVID-19: a clinical trial

Efficacy of Brazilian green propolis (EPP-AF®) as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial

Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19

Coronavirus biology and replication: implications for SARS-CoV-2

The SARS-CoV-2 main protease as drug target

RNA-dependent RNA polymerase as a target for COVID-19 drug discovery

Molecular and cellular mechanisms of the effects of propolis in inflammation, oxidative stress and glycemic control in chronic diseases

Propolis: propolis, bee glue, bee product, honey SAR-CoV-2: SAR-CoV-2, severe acute respiratory syndrome coronavirus 2, COVID-19, coronavirus, coronavirus disease, novel coronavirus, 2019-nCoV, COVID-2019 pneumonia Search strategy PubMed: ("SAR-CoV-2" OR "severe acute respiratory syndrome coronavirus 2" OR "COVID-19" OR "coronavirus" OR "coronavirus disease" OR "novel coronavirus" OR "2019-nCoV" OR "COVID-2019 pneumonia") AND ("propolis" OR "bee glue" OR "bee product" OR "honey") Scopus: ("SAR-CoV-2" OR "severe acute respiratory syndrome coronavirus 2" OR "COVID-19" OR "coronavirus" OR "coronavirus disease" OR

Investigation of potential inhibitor properties of ethanolic propolis extracts against ACE-II receptors for COVID-19 treatment by molecular docking study

Evaluating the potency of Sulawesi propolis compounds as ACE-2 inhibitors through molecular docking for COVID-19 drug discovery preliminary study

Identifying propolis compounds potential to be COVID-19 therapies by targeting SARS-CoV-2 main protease

Potential anti-COVID-19 activity of Egyptian propolis using computational modeling

In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

Optimization and evaluation of propolis liposomes as a promising therapeutic approach for COVID-19

Molecular interaction analysis of Sulawesi propolis compounds with SARS-CoV-2 main protease as preliminary study for COVID-19 drug discovery

In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes

In silico evaluation of flavonoids as effective antiviral agents on the spike glycoprotein of SARS-CoV-2

Antiviral activity of Brazilian green propolis extract against SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection: case report and review

Zorlu D. COVID-19 and Anatolian propolis: a case report

Promising preventive and therapeutic effects of TaibUVID nutritional supplements for COVID-19 pandemic: towards better public prophylaxis and treatment (a retrospective study)

Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): a multi-center placebo-controlled randomized clinical trial

The effect of propolis plus Hyoscyamus niger L. methanolic extract on clinical symptoms in patients with acute respiratory syndrome suspected to COVID-19: a clinical trial

Efficacy of Brazilian green propolis (EPP-AF®) as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial

Witoo Dilokthornsakul, Ramanya Kosiyaporn, Rattanamanee Wuttipongwaragon, Piyameth Dilokthornsakul

Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Mueang, Phitsanulok 65000, Thailand

Ashraf et al. [13] Kosari et al. [14] Silveira et al. [15] Domain 1: randomization process Low Some concerns High