All Studies Meta Analysis Recent:

All-trans retinoic acid acts as a dual-purpose inhibitor of SARS-CoV-2 infection and inflammation

Huang et al., Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2024.107942

Jan 2024

Post
Facebook

Source PDF All Studies Meta AnalysisMeta

Vitamin A for COVID-19

39th treatment shown to reduce risk in June 2023

^*, now known with p = 0.031 from 13 studies.

Lower risk for recovery and cases.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19early.org

In Vitro and In Silico study showing that all-trans retinoic acid (an active metabolite of vitamin A) inhibits the entry and replication of SARS-CoV-2 by binding to ACE2 / 3CL^pro / RdRp / helicase / 3′-to-5′ exonuclease, and reduces excessive inflammation induced by SARS-CoV-2.

10 preclinical studies support the efficacy of vitamin A for COVID-19:

4 In Silico studies Chakraborty, Huang, Li, Pandya

5 In Vitro studies DiGuilio, Huang, Moatasim, Morita, Tong

1 In Vivo animal study Franco

Vitamin A has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function EFSA, Galmés, Galmés (B). Vitamin A has potent antiviral activity against SARS-CoV-2 in both human cell lines and human organoids of the lower respiratory tract (active metabolite all-trans retinoic acid, ATRA) Tong, is predicted to bind critical host and viral proteins for SARS-CoV-2 and may compensate for gene expression changes related to SARS-CoV-2 Chakraborty, Huang, Pandya, may be beneficial for COVID-19 via antiviral, anti-inflammatory, and immunomodulatory effects according to network pharmacology analysis Li, reduces barrier compromise caused by TNF-α in Calu-3 cells DiGuilio, inhibits mouse coronavirus replication Franco, may stimulate innate immunity by activating interferon responses in an IRF3-dependent manner (ATRA) Franco, may reduce excessive inflammation induced by SARS-CoV-2 Huang, shows SARS-CoV-2 antiviral activity In Vitro Huang, Moatasim, Morita, is effective against multiple SARS-CoV-2 variants in Calu-3 cells Morita, and inhibits the entry and replication of SARS-CoV-2 via binding to ACE2 / 3CLpro / RdRp / helicase / 3′-to-5′ exonuclease Huang.

Important missing comments or errors? Let us know.

1. Chakraborty et al., In-silico screening and in-vitro assay show the antiviral effect of Indomethacin against SARS-CoV-2, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105788.sciencedirect.com, doi.org.

2. DiGuilio et al., The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function, Experimental Lung Research, doi:10.1080/01902148.2023.2193637.tandfonline.com, doi.org.

3. EFSA, Scientific Opinion on the substantiation of health claims related to vitamin A and cell differentiation (ID 14), function of the immune system (ID 14), maintenance of skin and mucous membranes (ID 15, 17), maintenance of vision (ID 16), maintenance of bone (ID 13, 17), maintenance of teeth (ID 13, 17), maintenance of hair (ID 17), maintenance of nails (ID 17), metabolism of iron (ID 206), and protection of DNA, proteins and lipids from oxidative damage (ID 209) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2009.1221.europa.eu, doi.org.

4. Franco et al., Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK, Viruses, doi:10.3390/v16010140.mdpi.com, doi.org.

5. Galmés et al., Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations, Nutrients, doi:10.3390/nu14112254.mdpi.com, doi.org.

6. Galmés (B) et al., Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, Nutrients, doi:10.3390/nu12092738.mdpi.com, doi.org.

7. Huang et al., All-trans retinoic acid acts as a dual-purpose inhibitor of SARS-CoV-2 infection and inflammation, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2024.107942.sciencedirect.com, doi.org.

8. Li et al., Revealing the targets and mechanisms of vitamin A in the treatment of COVID-19, Aging, doi:10.18632/aging.103888.aging-us.com, doi.org.

9. Moatasim et al., Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E, Microorganisms, doi:10.3390/microorganisms11112777.mdpi.com, doi.org.

10. Morita et al., All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity, Viruses, doi:10.3390/v13081669.mdpi.com, doi.org.

11. Pandya et al., Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951.sciencedirect.com, doi.org.

12. Tong et al., A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry, mBio, doi:10.1128/mbio.01485-22.asm.org, doi.org.

Huang et al., 3 Jan 2024, peer-reviewed, 7 authors. Contact: leijian@scu.edu.cn, hinchu@hku.hk, yangsy@scu.edu.cn.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Vitamin A All

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Chong Huang, Huiping Shuai, Jingxin Qiao, Yuxin Hou, Rui Zeng, Anjie Xia, Lingwan Xie, Zhen Fang, Yueyue Li, Chaemin Yoon, Qiao Huang, Bingjie Hu, Jing You, Baoxue Quan, Xiu Zhao, Nihong Guo, Shiyu Zhang, Ronggang Ma, Jiahao Zhang, Yifei Wang, Ruicheng Yang, Shanshan Zhang, Jinshan Nan, Haixing Xu, Falu Wang, Jian Lei, Hin Chu, Shengyong Yang

Signal Transduction and Targeted Therapy, doi:10.1038/s41392-023-01392-w

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (M pro ). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance M pro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

AUTHOR CONTRIBUTIONS S.Y., H.C., and J.L. conceived research; and C.H. performed the drug design; C.H., A.X., and Z.F. with the assistance of Q.H., J.Y., B.Q., N.G., S.Z., R.M., J.Z., S.Z., J.N., H.X., and F.W. performed the chemical synthesis; R.Z., L.X., J.Q., and X.Z. performed gene expression, protein purification and crystallization experiments; R.Z., L.X., and J.L. determined the crystal structures; J.Q. and Y.L. performed high-throughput screening, enzymatic activity and inhibition assays, IC 50 measurements, DSF assays, cytotoxicity assays and in vivo toxicity assays; H.S., Y.H., C.Y., and B.H. performed in vitro and in vivo antiviral assays; S.Y., J.L., and H.C. with the assistance of C.H., H.S., J.Q., and R.Z. wrote and revised the manuscript. All authors have read and approved the article. ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41392-023-01392-w. Competing interests: All authors declared no competing interests. S.Y. is the member of editorial board, he has not been involved in the process of the manuscript handling.

References

Afonine, Towards automated crystallographic structure refnement with phenix, refne. Acta Crystallogr. D. Biol. Crystallogr

Anand, Ziebuhr, Wadhwani, Mesters, Hilgenfeld, Coronavirus main proteinase (3CL pro ) structure: basis for design of anti-SARS drugs, Science

Andrews, Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant, N. Engl. J. Med

Bricogne, None, BUSTER version

Cao, 4 and BA.5 escape antibodies elicited by Omicron infection, Nature

Chan, Virological features and pathogenicity of SARS-CoV-2 Omicron BA.2, Cell Rep. Med

Chu, Host and viral determinants for efficient SARS-CoV-2 infection of the human lung, Nat. Commun

Dai, Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease, Science

Emsley, Features and development of Coot, Acta Crystallogr. D. Biol. Crystallogr

Evans, How good are my data and what is the resolution?, Acta Crystallogr. D. Biol. Crystallogr

Fu, Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease, Nat. Commun

Garcia-Beltran, mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant, Cell

Halfmann, SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters, Nature

Han, Structure-based optimization of ML300-derived, noncovalent inhibitors targeting the severe acute respiratory syndrome coronavirus 3CL protease (SARS-CoV-2 3CL pro ), J. Med. Chem

Hegyi, Ziebuhr, Conservation of substrate specificities among coronavirus main proteases, J. Gen. Virol

Heilmann, SARS-CoV-2 3CL pro mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376, Sci. Transl. Med

Hilgenfeld, From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design, FEBS J

Hu, Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir, bioRxiv, doi:10.1101/2022.06.28.497978

Hu, Spike mutations contributing to the altered entry preference of SARS-CoV-2 Omicron BA.1 and BA.2, Emerg. Microbes Infect

Iketani, Antibody evasion properties of SARS-CoV-2 Omicron sublineages, Nature

Iketani, Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir, Nature

Jin, Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur, Nat. Struct. Mol. Biol

Jochmans, The substitutions L50F, E166A and L167F in SARS-CoV-2 3CL pro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir, mBio

Kabsch, Xds, None, Acta Crystallogr. D. Biol. Crystallogr

Khailany, Safdar, Ozaslan, Genomic characterization of a novel SARS-CoV-2, Gene Rep

Liu, Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2, Nature

Lopez Bernal, Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant, N. Engl. J. Med

Lu, Su, Yang, Jiang, Antivirals with common targets against highly pathogenic viruses, Cell

Mannar, SARS-CoV-2 Omicron variant: antibody evasion and cryo-EM structure of spike protein-ACE2 complex, Science

Moghadasi, Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors, bioRxiv, doi:10.1101/2022.08.07.503099

Mohapatra, Twin of Omicron and Delta variants triggering a tsunami wave of ever high surges in COVID-19 cases: a challenging global threat with a special focus on the Indian subcontinent, J. Med. Virol

Noske, Structural basis of nirmatrelvir and ensitrelvir resistance profiles against SARS-CoV-2 Main Protease naturally occurring polymorphisms, J. Biol. Chem

Owen, An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19, Science

Planas, Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization, Nature

Qiao, SARS-CoV-2 M pro inhibitors with antiviral activity in a transgenic mouse model, Science

Quan, An orally available M pro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron, Nat. Microbiol

Rathnayake, 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice, Sci. Transl. Med

Saad-Roy, Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years, Science

Sacco, Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M pro and cathepsin, L. Sci. Adv

Sasi, Predicting antiviral resistance mutations in SARS-CoV-2 main protease with computational and experimental screening, Biochemistry

Shuai, Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron, Nature

Shuai, Emerging SARS-CoV-2 variants expand species tropism to murines, EBioMedicine

Suzuki, Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant, Nature

Tuekprakhon, Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum, Cell

Unoh, Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19, J. Med. Chem

Wahl, SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801, Nature

Williamson, Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2, Nature

Wu, A new coronavirus associated with human respiratory disease in China, Nature

Wu, Yin, Jiang, Xu, Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19, Acta Pharmacol. Sin

Xie, Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2, Cell Res

Yan, Florian, Why remdesivir failed: preclinical assumptions overestimate the clinical efficacy of remdesivir for COVID-19 and Ebola, Antimicrob. Agents Chemother

Zhang, Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients, Signal Transduct. Target Ther

Zhang, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science

Zhou, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature

Zhou, Nirmatrelvir resistant SARS-CoV-2 variants with high fitness in vitro, Sci Adv

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ 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. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0