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@CovidAnalysis

COVID-19 treatment: systemic agents

• Many systemic agents reduce risk

@CovidAnalysis, October 1, 2025
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We do not provide medical advice. No treatment is 100% effective, and all may have side effects. Protocols combine multiple treatments. Consult a qualified physician for personalized risk/benefit analysis.
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Systemic agents
 
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Over 10,000 compounds predicted to reduce risk—SARS-CoV-2 easily disabled SARS-CoV-2 infection and replication involves a complex interplay of over 250 host and viral proteins and other factors1-8, providing many therapeutic targets. Scientists have identified 10,285+ compounds9 potentially beneficial for COVID-19. Hundreds of compounds inhibit SARS-CoV-2 in vitro, including many with known pharmacokinetics and proven safety.
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Efficacy confidence - low-cost systemic
Curcuminp<0.00000001
Hydroxychloroquinep<0.00000001
Ivermectinp<0.00000001
Melatoninp=0.00000001
Metforminp<0.00000001
Antiandrogensp=0.00000006
Azvudinep=0.0000001
Colchicinep=0.0000001
Probioticsp=0.000001
N-acetylcysteinep=0.00003
Antihistamine H1RAsp=0.00005
Fluvoxaminep=0.0001
Nigella Sativap=0.0002
Famotidinep=0.0003
TMPRSS2 inhibitorsp=0.0007
Quercetinp=0.002
Efficacy confirmed March 2020 (HCQ)(a),13
P-values indicate the confidence that studies show a significant effect. p=0.05 is the typical threshold for significance, with lower values indicating higher confidence. See the individual analyses for details of efficacy for specific outcomes and conditions.
Low-cost systemic treatments Many low-cost treatments have been identified as effective10,11,14-1027.
❝
if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the circle of social hell…
Scott Alexander1028
Politicization Hydroxychloroquine and ivermectin have become the most politicized treatments of all time. As Scott Alexander said1028: "if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in the world will shout 'horse dewormer!' at you and compare you to Josef Mengele."
❝
it is often possible to make clinical trials come out pretty much any way you want
Marcia Angell, former NEJM editor1029
Hydroxychloroquine Extensive preclinical research supports efficacy1030-1064. Viruses like SARS-CoV-2 that depend on low pH for endosomal entry1065,1066 can be inhibited with endosomal acidification inhibitors like HCQ(b),1042,1055,1066. Direct clinical measurement shows that HCQ reaches therapeutic concentrations in COVID-19 patients1067, and analysis of lung cells from COVID-19 patients shows inhibition in early target cell types1068,1069.
The largest HCQ/CQ RCT, withheld over two years, shows 57% lower PCR+ COVID-19 (p=0.0002)(c),10.
Analysis of 424 controlled clinical studies10,11,121-545 shows strong evidence for efficacy with early treatment (p<0.00000001) and prophylaxis (p<0.00000001), confirmed in multiple additional meta analyses422,1070-1077. The largest HCQ/CQ RCT—the 4,652 patient Oxford/MORU COPCOV RCT—shows 57% lower symptomatic PCR+ COVID-19 (p=0.0002, results withheld for over two years)(c),10. In 2021 Naggie et al.489 showed that HCQ prophylaxis significantly reduced COVID-19 cases based on 2 US RCTs. This is now known with p=0.00004 for RCTs and p=0.00000001 for observational studies. The Oxford PRINCIPLE RCT, withheld for 5 years, shows significantly faster recovery with HCQ(d),11.
HCQ shows poor results with late treatment and excessive dosage, and the combination shows harm. Late-stage treatment may enhance viral egress via lysosomal deacidification(e),1078,1079. Research also suggests potential cardioprotective effects at lower doses, but cardiotoxicity with excessive dosage1046. Combined use of HCQ and remdesivir is contraindicated1080, but was commonly done. The RECOVERY trial, key to the worldwide campaign against HCQ, used very late treatment with an excessive toxic dose185. Strong evidence for harm with the dose used was known from a dose comparison RCT on April 241081. It is unclear how the trial, with reported IDMC interim reviews every two weeks, could justify starting and continuing this dose until June 5.
HCQ studies focused on late treatment (90%). Early/preventive trials—more likely to be positive—did not report results at a 3x higher rate.
Studies for HCQ are inconsistent with the logical use of antivirals. 90% of treatment studies analyzed late treatment, 5+ days after the onset of symptoms546. This makes it easy to generate meta analyses showing poor efficacy by including large late treatment studies1082, although the results are not relevant to recommended usage. Results have not been reported for 37 RCTs1083-1119, and an additional 65 RCTs were terminated with <30 patients1120-1178.
HCQ was the first treatment confirmed effective1179, however alternatives may offer advantages. Lung pharmacokinetics show high inter-individual variability1067; dosage is relatively challenging, with dependence on cholesterol1049, lung pH1040, and renal impairment1040, delayed attainment of therapeutic concentrations, and a relatively narrow range of regimens showing efficacy while limiting side effects; and ~2.5%1180 of patients may have contraindications. Longer-term use of endosomal acidification modifiers raises concern for potential off-target effects, including disruption of cellular processes, impaired lysosomal function, reduced immune response1181, and altered cellular signaling. Fake tablets are common in some locations1182-1184.
Ivermectin
The largest ivermectin RCT shows faster recovery with probability >0.999 and 36% lower long COVID, p<0.0001, despite extreme bias and very suboptimal design(f),99.
Analysis of 106 clinical studies14-119 shows strong evidence for efficacy (p<0.00000001), confirmed in multiple additional meta analyses1185-1194. Ivermectin shows efficacy in RCTs for prophylaxis, early treatment, and late treatment. Major RCTs claiming no benefit actually show positive results, despite extreme bias1195.
The largest RCT, with a design highly favoring finding no efficacy, found superiority with probability >0.999 for recovery(f),99. Improved recovery is strongly associated with lower mortality, p<0.00000000001(f),99. The trial also found 36% lower long COVID (p<0.0001) despite very suboptimal use(f),99.
A post-exposure prophylaxis RCT shows 96% lower cases with high viral load with ivermectin118. A long COVID RCT shows 4x faster resolution of anosmia92.
Extensive preclinical research supports efficacy(g),1196,1198-1200,1205,1207-1233,1235-1286. Ivermectin also has the most carefully analyzed evidence base in history, resulting in the retraction of a few studies which has improved the quality of the evidence base, and improved the dose-response and treatment delay-response relationships. However the analysis team showed strong bias, focusing only on issues with positive results1287-1289, and disregarding flaws and fraud in the major trials claiming no effect120. For example, the main author claims the Together Trial was "incredibly well-done" and a "masterpiece of science" despite the trial reporting multiple impossible numbers, blinding being broken with external sharing during the trial, randomization failure, refusal to share data despite pledging to, no response from the authors, and many protocol violations39.
Optimal use of ivermectin may involve synergy with combined treatments, administration taking into account the lipophilic nature, and sublingual, spray, or inhaled formulations for direct treatment to the respiratory tract. Pharmacokinetics show significant inter-individual variability1290. Injectable formulations may reduce variability and provide faster onset of action1275. Liposomal formulations show increased antiviral activity and lower cytotoxicity1270. Synergistic results are seen with polytherapy1267,1269,1274. Efficacy varies depending on the manufacturer1291, underdosed and contaminated ivermectin is common1292-1295, and fake tablets with no active ingredient have been reported1296.
❝
There is a clear signal that IVM works in COVID patients…
Ed Mills, Together Trial co-principal investigator1297
Systemic vs. topical application Dosing and minimizing side effects may be easier with inhaled or nasal/oral spray formulations, which have been widely proposed for HCQ1044,1298-1303 and ivermectin92,1260,1281,1282,1286,1304-1306. These formulations may prevent progression to other tissues and improve utility for less severe cases without significant progression beyond the respiratory tract. All studies to date reporting clinical results for HCQ/ivermectin treatment with inhaled/spray formulations report significant positive results36,92,771,1303.
Metformin 107 metformin clinical studies419,425,547-651 show efficacy, confirmed in multiple additional meta analyses1307-1328. Studies also show efficacy for acute respiratory failure1329 and influenza A1330. Extensive preclinical research supports efficacy(h),554,632,1240,1331-1344.
Antiandrogens 49 antiandrogen clinical studies653-701 show efficacy, confirmed in multiple additional meta analyses1345,1346. Preclinical research supports efficacy1347-1350. Potential mechanisms include inhibition of TMPRSS2 expression, reduction of androgen-mediated viral entry, modulation of the immune response, and attenuation of inflammation.
Antihistamine H1RAs 17 antihistamine H1RA clinical studies703-719 show efficacy. Extensive preclinical research supports efficacy705,713,1351-1358.
Curcumin 28 curcumin clinical studies751-778 show efficacy, confirmed in multiple additional meta analyses1359-1363. Extensive preclinical research supports efficacy(t),1031,1043,1238,1240,1265,1364-1407. Curcumin has low bioavailability and stability1408—COVID-19 efficacy may depend heavily on advanced formulations1409 for improved bioavailability.
Melatonin 20 melatonin clinical studies780-799 show efficacy, confirmed in multiple additional meta analyses1410-1416. Extensive preclinical research supports efficacy(u),1417-1424. Potential mechanisms include antioxidant, anti-inflammatory, and antithrombotic effects, immune modulation, regulation of autophagy, modulation of the renin-angiotensin system, promotion of sleep and circadian rhythm, and mitigation of cytokine storm.
Colchicine 57 colchicine clinical studies419,801-856 show efficacy, confirmed in multiple additional meta analyses1425-1434. Preclinical research supports efficacy1393. Potential mechanisms include direct antiviral activity, immunomodulatory and anti-inflammatory effects, cardioprotective effects, and prevention of microvascular thrombosis. Results are poor with very late treatment819—risks due to side effects may exceed benefits.
Probiotics 28 probiotics clinical studies858-885 show efficacy, confirmed in multiple additional meta analyses1435,1436. Studies also show efficacy for respiratory tract infections1437 and the common cold1438. Preclinical research supports efficacy1439,1440.
NAC 24 N-acetylcysteine clinical studies925-948 show efficacy, confirmed in multiple additional meta analyses1441,1442. Efficacy has also been shown for influenza1443. Extensive preclinical research supports efficacy(v),1240,1393,1420,1444-1454.
Fluvoxamine 21 fluvoxamine clinical studies950-970 show efficacy, confirmed in multiple additional meta analyses1455-1463. See Kirsch et al. for additional evidence and analysis. Preclinical research supports efficacy(w),1465-1468. Potential mechanisms include ASM inhibition, σ-1 receptor activation, antiplatelet effects, endolysosomal interference, HO-1 increase, reduced cytokine storm, and elevated melatonin.
Azvudine 37 azvudine clinical studies887-923 show efficacy, confirmed in multiple additional meta analyses1469-1473. Preclinical research supports efficacy1474.
Nigella Sativa 14 nigella sativa clinical studies972-985 show efficacy, confirmed in multiple additional meta analyses1475,1476. Extensive preclinical research supports efficacy1031,1477-1494. Potential mechanisms include direct antiviral activity, and immunomodulatory, antioxidant, and anti-inflammatory action.
Famotidine 30 famotidine clinical studies414,419,987-1013 show efficacy. Preclinical research supports efficacy1495. Potential mechanisms include direct antiviral activity, anti-inflammatory effects and reduced cytokine release, reduced acidity altering conditions for viral replication, immune modulation, and anticoagulant effects.
TMPRSS2 inhibitors 29 TMPRSS2 inhibitor clinical studies721-749 show efficacy. Extensive preclinical research supports efficacy1030,1238,1243,1496-1503.
Quercetin 12 quercetin clinical studies1015-1026 show efficacy, confirmed in multiple additional meta analyses1504,1505. Extensive preclinical research supports efficacy(ar),1031,1033,1238,1365,1369,1373,1378,1381,1382,1390,1395,1506,1508-1565. Potential mechanisms include direct antiviral activity, antioxidant and anti-inflammatory activity, and immune support. COVID-19 efficacy may depend heavily on advanced formulations for improved bioavailability.
Systemic antivirals may be less applicable to low-risk infections As SARS-CoV-2 has evolved, the frequency of serious infections has reduced. Systemic antivirals may have a more limited effect if infection does not spread beyond the upper respiratory tract.
Protocols combine multiple treatments No single treatment is guaranteed to be effective and safe for a specific individual. Leading evidence-based protocols combine multiple treatments.
c19early.org
Combined treatments increase efficacy
Monotherapy33% [30‑36%]
Polytherapy68% [57‑77%]
 Meta analysis of early treatment studies.
Complementary/synergistic actions, viral evolution, escape risk suggest polytherapy There are many complementary mechanisms of action, and studies show complementary and synergistic effects with polytherapy84,1059,1267,1269,1274,1277,1500,1501,1566-1574. For example, Jitobaom et al.1269 shows >10x reduction in IC50 with ivermectin and niclosamide, an RCT by Said et al.1569 showed the combination of nigella sativa and vitamin D was more effective than either alone, and an RCT by Wannigama et al.961 showed improved results with fluvoxamine combined with additional treatments, compared to fluvoxamine alone.
SARS-CoV-2 can rapidly acquire mutations altering infectivity, disease severity, and drug resistance even without selective pressure1575-1582. Antigenic drift can undermine more variant-specific treatments like monoclonal antibodies and more specific antivirals. Treatment with targeted antivirals may select for escape mutations1583. The efficacy of treatments varies depending on cell type1584 due to differences in viral receptor expression, drug distribution and metabolism, and cell-specific mechanisms. Efficacy may also vary based on genetic variants1585-1595.
Variable efficacy across variants, cell types, tissues, and host genetics, along with the complementary and synergistic actions of different treatments, all point to greater efficacy with polytherapy. In many studies, the standard of care given to all patients includes other treatments—efficacy seen in these trials may rely in part on synergistic effects. Less variant specific treatments and polytherapy targeting multiple viral and host proteins may be more effective. Meta analysis of all early treatment trials shows 68% [57‑77%] lower risk for studies using combined treatments, compared to 33% [30‑36%] for single treatments.
 
Footnotes
a.
Defined as ≥3 studies showing ≥10% improvement or >0% harm with statistical significance in meta analysis.
b.
The efficacy of endosomal entry inhibitors varies across SARS-CoV-2 variants, depending on their reliance on the endosomal pathway for entry. SARS-CoV-2 uses two major pathways for host cell entry: endosomal entry via cathepsin proteases and TMPRSS2-mediated plasma membrane fusion. Studies show increased reliance on TMPRSS2-mediated entry for the Delta variant compared to the original strain. Conversely, Omicron variants have shown significantly greater reliance on endosomal entry, suggesting increased efficacy of endosomal acidification inhibitors. Specific sub-variants may vary. A dual-inhibition strategy targeting both pathways may be preferred.
c.
COPCOV has the largest number of treated patients of all HCQ/CQ RCTs. Authors include their own meta analysis of RCTs confirming significant efficacy. Due to the politicization, the most relevant data is hidden within the body of the paper and the supplementary data. Note that the post-hoc serology based analysis is unreliable as discussed in the paper—due to the high false negative rate of serum/DBS serology, false negative baseline serology may account for many/most of the seroconversion cases10.
d.
The other arms of this trial confirm that the efficacy is not due to the open label design11. Significant improvement is seen consistently across all symptoms, and across all variants of the recovery outcome.
e.
When administered late in infection, HCQ may enhance viral egress by further increasing lysosomal pH beyond the effect of ORF3a's water channel activity, thereby promoting lysosomal exocytosis, inactivating degradative enzymes, and facilitating the release of SARS-CoV-2 particles into the extracellular environment1078,1079.
f.
Page 358 in the appendix shows 36% lower ongoing persistent COVID-19 specific symptoms (p<0.0001) when combining the individual symptom results. Authors report a 28% reduction (p=0.015), not mentioned in the abstract or conclusion. This appears to be a one of any symptom analysis, effectively increasing the weight of the more common “fatigue”, reducing the perceived effect (the difference does not appear to be due to adjustments - the adjustments in Table S6 to Table S39 make minimal difference). This is for very late and poorly administered treatment taken by only 89% of patients in a relatively low-risk population - benefits may be much greater with recommended usage and in high-risk patients. Prof. Sander Greenland demonstrates12 that the Bayesian model applied an extremely tight, null-centred prior that was never reported in the paper. This prior pulls the frequentist hazard ratio for time-to-recovery down and slashes the posterior probability that the benefit reaches the trial's own “clinically meaningful” threshold of HR≥1.2. Even with the shrinkage, the posterior probability of any benefit exceeds 0.9999, well above the protocol's 0.99 superiority bar, however authors label ivermectin “unlikely to provide clinically meaningful improvement.” Greenland argues that the unexplained prior acts like a hidden penalty, lacks empirical justification, and biases the analysis toward the null, thereby allowing the authors to downplay results their own decision rules would otherwise classify as superior. Author notes the strong priors are not justified by previous trials and suggests that they reflect social pressure to discredit ivermectin.
g.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N71196, Dengue1197-1199, HIV-11198, Simian virus 401200, Zika1199,1201,1202, West Nile1202, Yellow Fever1203,1204, Japanese encephalitis1203, Chikungunya1204, Semliki Forest virus1204, Human papillomavirus1205, Epstein-Barr1205, BK Polyomavirus1206, and Sindbis virus1204. Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins1196,1198,1200,1207, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing1208, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination1209,1210, shows dose-dependent inhibition of wildtype and omicron variants1211, exhibits dose-dependent inhibition of lung injury1212,1213, may inhibit SARS-CoV-2 via IMPase inhibition1199, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation1214, inhibits SARS-CoV-2 3CLpro1215, may inhibit SARS-CoV-2 RdRp activity1216, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages1217, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation1218, may interfere with SARS-CoV-2's immune evasion via ORF8 binding1219, may inhibit SARS-CoV-2 by disrupting CD147 interaction1220-1223, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-191224,1225, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage1226, may minimize SARS-CoV-2 induced cardiac damage1227,1228, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation1229, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1230, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways1231, increases Bifidobacteria which play a key role in the immune system1232, has immunomodulatory1233 and anti-inflammatory1234,1235 properties, and has an extensive and very positive safety profile1236.
h.
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI)1331. Metformin inhibits SARS-CoV-2 in vitro554,1332, minimizes LPS-induced cytokine storm in a mouse model1333, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS632, may protect against SARS-CoV-2-induced neurological disorders1334, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation1335, reduces UUO and FAN-induced kidney fibrosis632, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells632, may reduce inflammation, oxidative stress, and thrombosis via regulating glucose metabolism1336, attenuates spike protein S1-induced inflammatory response and α-synuclein aggregation1337, may reduce COVID-19 severity and long COVID by inhibiting NETosis via suppression of protein kinase C activation1338, enhances interferon responses and reduces SARS-CoV-2 infection and inflammation in diabetic models by suppressing HIF-1α signaling1339, may improve COVID-19 outcomes by preventing VDAC1 mistargeting to the plasma membrane, reducing ATP loss, and preserving immune cell function during cytokine storm1340, reduces hyperglycemia-induced hepatic ACE2/TMPRSS2 up-regulation and SARS-CoV-2 entry1341, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity1342.
i.
The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
j.
The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.
k.
The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
l.
RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
m.
The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
n.
The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
o.
The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
p.
Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.
q.
The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
r.
The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
s.
Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
t.
In silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spike(i),1238,1364-1369 (and specifically the receptor binding domain(j),1370-1374), Mpro(k),1238,1365,1366,1368,1369,1371-1373,1375-1382, RNA-dependent RNA polymerase(l),1238,1369,1372,1373,1383, PLpro(m),1238, ACE2(n),1031,1367,1374,1381, nucleocapsid(o),1265,1384, nsp10(p),1265, and helicase(q),1385 proteins, and inhibition of spike-ACE2 interaction(r),1386. In vitro studies demonstrate inhibition of the spike(i),1043 (and specifically the receptor binding domain(j),1387), Mpro(k),1043,1382,1388,1389, ACE2(n),1387, and TMPRSS2(s),1387 proteins, and inhibition of spike-ACE2 interaction(r),1386,1390. Curcumin decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells1391, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress1392, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts1393, is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants1370, lowers ACE2 and STAT3, curbing lung inflammation and ARDS in preclinical COVID-19 models1394, inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity1395, has direct virucidal action by disrupting viral envelope integrity1396, and can function as a photosensitizer in photodynamic therapy to generate reactive oxygen species that damage the virus1396.
u.
Melatonin may restore altered redox homeostasis in COVID-191417, modulates type III interferon responses and reduces inflammatory cytokine production in TLR3 receptor agonist stimulated viral inflammation while preserving tissue integrity1418, and negatively regulates genes critical for viral entry in lung tissue, including reduced expression of FURIN and components of the CD147 complex, while potentially disrupting TMPRSS2/ACE2-mediated entry mechanisms1419. Melatonin reduces oxidative stress, inhibits NET formation, and protects tissues through anti-inflammatory and antioxidant actions1420.
v.
Severe COVID-19 is marked by endotheliopathy with elevated von Willebrand factor (VWF) levels and platelet/VWF-rich microthrombi; N-acetylcysteine can reduce VWF multimers and lyse VWF-dependent clots in vivo, potentially helping to alleviate thrombosis associated with COVID-191444-1446. N-acetylcysteine shows dose-dependent inhibition of SARS-CoV-21447-1449, shows anti-inflammatory and immunomodulatory effects against SARS-CoV-2-induced immune responses in combination with bromelain1450, suppressed virus-induced reactive oxygen species and blocked viral replication in a humanized mouse model and in human lung cells1451, may limit COVID-19 induced cardiac damage by boosting cellular antioxidant defenses and potentially mitigating the oxidative stress caused by spike protein-induced ROS production in cardiac fibroblasts1393, and reduces disulfide bonds in proteins and exhibits antioxidant properties that may inhibit viral replication and modulate inflammatory responses1452. NAC may be beneficial for COVID-19 by replenishing glutathione stores and reinforcing the glutathione peroxidase-4 pathway to inhibit ferroptosis, an oxidative stress-induced cell death pathway implicated in COVID-191453. NAC reinforces glutathione levels, reduces ROS, and minimizes ferroptosis and cytokine storm1420.
w.
Fluvoxamine may inhibit SARS-CoV-2 cell entry by preventing the formation of ceramide platforms that facilitates viral uptake1465, may help restore autophagic processes disrupted by NSP6, thereby reducing SARS-CoV-2 replication and improving host cellular defenses1466, and may reduce COVID-19 thrombotic complications by inhibiting serotonin reuptake and decreasing platelet activation1467.
x.
The endoribonuclease, also known as NendoU or nsp15, cleaves specific sequences in viral RNA which may help the virus evade detection by the host immune system. Inhibition may hinder the virus's ability to mask itself from the immune system, facilitating a stronger immune response.
y.
The NSP16/10 complex consists of non-structural proteins 16 and 10, forming a 2'-O-methyltransferase that modifies the viral RNA cap structure. This modification helps the virus evade host immune detection by mimicking host mRNA, making NSP16/10 a promising antiviral target.
z.
Cathepsin L is a host lysosomal cysteine protease that can prime the spike protein through an alternative pathway when TMPRSS2 is unavailable. Dual targeting of cathepsin L and TMPRSS2 may maximize disruption of alternative pathways for virus entry.
aa.
Wingless-related integration site (Wnt) ligand 3 is a host signaling molecule that activates the Wnt signaling pathway, which is important in development, cell growth, and tissue repair. Some studies suggest that SARS-CoV-2 infection may interfere with the Wnt signaling pathway, and that Wnt3a is involved in SARS-CoV-2 entry.
ab.
The frizzled (FZD) receptor is a host transmembrane receptor that binds Wnt ligands, initiating the Wnt signaling cascade. FZD serves as a co-receptor, along with ACE2, in some proposed mechanisms of SARS-CoV-2 infection. The virus may take advantage of this pathway as an alternative entry route.
ac.
Low-density lipoprotein receptor-related protein 6 is a cell surface co-receptor essential for Wnt signaling. LRP6 acts in tandem with FZD for signal transduction and has been discussed as a potential co-receptor for SARS-CoV-2 entry.
ad.
The ezrin protein links the cell membrane to the cytoskeleton (the cell's internal support structure) and plays a role in cell shape, movement, adhesion, and signaling. Drugs that occupy the same spot on ezrin where the viral spike protein would bind may hindering viral attachment, and drug binding could further stabilize ezrin, strengthening its potential natural capacity to impede viral fusion and entry.
ae.
The Adipocyte Differentiation-Related Protein (ADRP, also known as Perilipin 2 or PLIN2) is a lipid droplet protein regulating the storage and breakdown of fats in cells. SARS-CoV-2 may hijack the lipid handling machinery of host cells and ADRP may play a role in this process. Disrupting ADRP's interaction with the virus may hinder the virus's ability to use lipids for replication and assembly.
af.
Neuropilin-1 (NRP1) is a cell surface receptor with roles in blood vessel development, nerve cell guidance, and immune responses. NRP1 may function as a co-receptor for SARS-CoV-2, facilitating viral entry into cells. Blocking NRP1 may disrupt an alternative route of viral entry.
ag.
EP300 (E1A Binding Protein P300) is a transcriptional coactivator involved in several cellular processes, including growth, differentiation, and apoptosis, through its acetyltransferase activity that modifies histones and non-histone proteins. EP300 facilitates viral entry into cells and upregulates inflammatory cytokine production.
ah.
Prostaglandin G/H synthase 2 (PTGS2, also known as COX-2) is an enzyme crucial for the production of inflammatory molecules called prostaglandins. PTGS2 plays a role in the inflammatory response that can become severe in COVID-19 and inhibitors (like some NSAIDs) may have benefits in dampening harmful inflammation, but note that prostaglandins have diverse physiological functions.
ai.
Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) is a chaperone protein that helps other proteins fold correctly and maintains their stability. HSP90AA1 plays roles in cell signaling, survival, and immune responses. HSP90AA1 may interact with numerous viral proteins, but note that it has diverse physiological functions.
aj.
Matrix metalloproteinase 9 (MMP9), also called gelatinase B, is a zinc-dependent enzyme that breaks down collagen and other components of the extracellular matrix. MMP9 levels increase in severe COVID-19. Overactive MMP9 can damage lung tissue and worsen inflammation. Inhibition of MMP9 may prevent excessive tissue damage and help regulate the inflammatory response.
ak.
The interleukin-6 (IL-6) pro-inflammatory cytokine (signaling molecule) has a complex role in the immune response and may trigger and perpetuate inflammation. Elevated IL-6 levels are associated with severe COVID-19 cases and cytokine storm. Anti-IL-6 therapies may be beneficial in reducing excessive inflammation in severe COVID-19 cases.
al.
The interleukin-10 (IL-10) anti-inflammatory cytokine helps regulate and dampen immune responses, preventing excessive inflammation. IL-10 levels can also be elevated in severe COVID-19. IL-10 could either help control harmful inflammation or potentially contribute to immune suppression.
am.
Vascular Endothelial Growth Factor A (VEGFA) promotes the growth of new blood vessels (angiogenesis) and has roles in inflammation and immune responses. VEGFA may contribute to blood vessel leakiness and excessive inflammation associated with severe COVID-19.
an.
RELA is a transcription factor subunit of NF-kB and is a key regulator of inflammation, driving pro-inflammatory gene expression. SARS-CoV-2 may hijack and modulate NF-kB pathways.
ao.
A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
ap.
A mouse model of obesity and severe insulin resistance leading to type 2 diabetes due to a mutation in the leptin receptor gene that impairs satiety signaling.
aq.
A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
ar.
In silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spike(i),1033,1238,1365,1369,1381,1506-1514 (and specifically the receptor binding domain(j),1373), Mpro(k),1033,1238,1365,1369,1373,1378,1381,1509,1510,1512,1515-1529, RNA-dependent RNA polymerase(l),1238,1369,1373,1512,1530,1531, PLpro(m),1238,1517,1522, ACE2(n),1031,1381,1508,1513,1517,1518,1532, TMPRSS2(s),1508, nucleocapsid(o),1238, helicase(q),1238,1516,1533, endoribonuclease(x),1506, NSP16/10(y),1534, cathepsin L(z),1535, Wnt-3(aa),1508, FZD(ab),1508, LRP6(ac),1508, ezrin(ad),1536, ADRP(ae),1033, NRP1(af),1513, EP300(ag),1537, PTGS2(ah),1518, HSP90AA1(ai),1518,1537, matrix metalloproteinase 9(aj),1538, IL-6(ak),1539,1540, IL-10(al),1539, VEGFA(am),1540, and RELA(an),1540 proteins, and inhibition of spike-ACE2 interaction(r),1541. In vitro studies demonstrate inhibition of the Mpro(k),1382,1524,1542,1543 protein, and inhibition of spike-ACE2 interaction(r),1390. Animal studies demonstrate efficacy in K18-hACE2 mice(ao),1544, db/db mice(ap),1545,1546, BALB/c mice(aq),1547, and rats1548. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice1547, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages1549, may block ACE2-spike interaction and NLRP3 inflammasome, limiting viral entry and inflammation1550, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity1395.
References
Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.
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