Innovation1 Biotech

Pioneering Research in Metabolic Biochemistry

Our scientific research has contributed significantly to the understanding of metabolic pathway modulation through targeted nutritional compounds. Publications by our scientific team, led by Dr. Dorit Arad, have established the foundation for our innovative approach.

Key Publications

Antiviral Studies

Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J.R., & Hilgenfeld, R. (2003). Coronavirus main proteinase (3CLpro) structure: Basis for design of anti-SARS drugs. Science, 300, 1763–1767.

Arad, D. (2022). The Value of 3CL Protease Inhibitor Supplementation in Long Haul Syndrome Patients. ResearchGate. https://www.researchgate.net/publication/362791461_VALUE_OF_3CL_PROTEASE_INHIBITOR_SUPPLEMENTATION_1_The_Value_of_3CL_Protease_Inhibitor_Supplementation_in_Long_Haul_Syndrome_Patients

Arad, D. (2022). Tollovid as Rescue Agent for Paxlovid Rebound in Acute Covid-19. ResearchGate. https://www.researchgate.net/publication/362387662_Tollovid_as_Rescue_Agent_for_Paxlovid_Rebound_in_Acute_Covid-19

Arad, D. (2022). Consequences of Microclot Pathophysiology Underlying Long COVID Improved with Tollovid Supplementation. ResearchGate. https://www.researchgate.net/publication/363565069_Consequences_of_Microclot_Pathophysiology_Underlying_Long_COVID_Improved_with_Tollovid_Supplementation

Arad, D. (2024). QCT-Based 3CL Protease Inhibitor: Tollovir. Preprints. https://www.preprints.org/manuscript/202407.1888/v1

Chen, H., Muhammad, I., Zhang, Y., Ren, Y., Zhang, R., Huang, X., et al. (2016). Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase. Archives of Virology, 161(12), 3269-3278.

Gyebi, G.A., Ogunro, O.B., Adegunloye, A.P., Ogunyemi, O.M., & Afolabi, S.O. (2021). Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): An in silico screening of alkaloids and terpenoids from African medicinal plants. Journal of Biomolecular Structure and Dynamics, 39, 3396–3408.

Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., et al. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582, 289–293.

Khan, M.T., Ali, A., Wang, Q., Irfan, M., Khan, A., Zeb, M.T., Zhang, Y.-J., Chinnasamy, S., & Wei, D.-Q. (2020). Marine natural compounds as potents inhibitors against the main protease of SARS-CoV-2—A molecular dynamic study. Journal of Biomolecular Structure and Dynamics, 39, 3627–3637.

Lee, J., Ko, S., & Kim, J.M. (2023). Unveiling the Potentiality of Shikonin Derivatives Inhibiting SARS-CoV-2 Main Protease by Molecular Dynamic Simulation Studies. Biomedicines, 11(3), 831.

Liu, H., Ye, F., Sun, Q., Liang, H., Li, C., Li, S., et al. (2020). Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Pharmacological Research, 157, 104820.

Mohamed, N.M., Ali, E.M., & AboulMagd, A.M. (2021). Ligand-based design, molecular dynamics, and ADMET studies of suggested SARS-CoV-2 Mpro inhibitors. RSC Advances, 11(8), 4523-38.

Nayak, M.K., Agrawal, A.S., Bose, S., Naskar, S., Bhowmick, R., Chakrabarti, S., et al. (2014). Antiviral activity of baicalin against influenza virus H1N1-pdm09 is due to modulation of NS1-mediated cellular innate immune responses. Journal of Antimicrobial Chemotherapy, 69(5), 1298-1310.

Roe, M.K., Junod, N.A., Young, A.R., Beachboard, D.C., & Stobart, C.C. (2021). Targeting novel structural and functional features of coronavirus protease nsp5 (3CLpro, Mpro) in the age of COVID-19. Journal of General Virology, 102, 001558.

Saha, P., Bose, S., Srivastava, A.K., Chaudhary, A.A., Lall, R., & Prasad, S. (2021). Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions. Molecules, 26, 6783.

Service, R.F. (2022). Bad news for Paxlovid? Resistance may be coming. Science, 377, 138–139.

Su, H., Yao, S., Zhao, W., Li, M., Liu, J., Shang, W., et al. (2021). Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode. Science China Life Sciences, 64(7), 1197-1200.

Su, H., Yao, S., Zhao, W., Li, M., Liu, J., Shang, W., et al. (2020). Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro. bioRxiv. https://www.biorxiv.org/content/10.1101/2020.04.13.038687v1

Su, H., Yin, M., Shen, J., Li, M., Zhang, T., Liu, J., et al. (2022). Crystal structure of SARS-CoV 3C-like protease with baicalein. Protein Science, 31(6), e4319.

Teli, D., Balar, P., Patel, K., Sharma, A., Chavda, V., & Vora, L. (2023). Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants. Metabolites, 13, 309.

Yang, S., Shen, J., Li, G., Wu, B., Guo, Y., Yu, Y., et al. (2022). Baicalein and Baicalin Inhibit SARS-CoV-2 RNA-Dependent-RNA Polymerase. Frontiers in Pharmacology, 13, 837290.

Zakaryan, H., Arabyan, E., Oo, A., & Zandi, K. (2017). Flavonoids: promising natural compounds against viral infections. Archives of Virology, 162(9), 2539-2551.

Zandi, K., Teoh, B.T., Sam, S.S., Wong, P.F., Mustafa, M.R., & Abubakar, S. (2012). Antiviral activity of four types of bioflavonoid against dengue virus type-2. Virology Journal, 9, 560.

Zhu, Q.C., Wang, Y., Liu, Y.P., Zhang, R.Q., Li, X., Su, W.H., et al. (2011). Inhibition of enterovirus 71 replication by chrysosplenetin and penduletin. European Journal of Pharmaceutical Sciences, 44(3), 392-398.

Anti-inflammatory Studies

Dinda, B., Dinda, S., DasSharma, S., Banik, R., Chakraborty, A., & Dinda, M. (2017). Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. European Journal of Medicinal Chemistry, 131, 68-80.

Fan, G.W., Zhang, Y., Jiang, X., Zhu, Y., Wang, B., Su, L., et al. (2013). Anti-inflammatory activity of baicalein in LPS-stimulated RAW264.7 macrophages via estrogen receptor and NF-κB-dependent pathways. Inflammation, 36(6), 1584-1591.

Gasparyan, A.Y., Ayvazyan, L., Blackmore, H., & Kitas, G.D. (2011). Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatology International, 31(11), 1409-1417.

Min, K.R., Hwang, B.Y., & Ro, J.S. (2008). Shikonins attenuate microglial inflammatory responses by inhibition of ERK, Akt, and NF-kappaB: neuroprotective implications. Journal of Neurochemistry, 107(2), 557-69.

Shindo, S., Hosokawa, Y., Hosokawa, I., Ozaki, K., & Matsuo, T. (2016). Shikonin Inhibits Inflammatory Cytokine Production in Human Periodontal Ligament Cells. Inflammation, 39, 1124–1129.

Suh, Y.A., Jo, S.Y., Lee, H.Y., & Lee, C. (2015). Inhibition of IL-8 reduces CXCR1/2 expression and invasion in androgen-independent prostate cancer cells. Prostate, 75(12), 1255-1265.

Tsai, C.L., Lin, Y.C., Wang, H.M., & Chou, T.C. (2014). Baicalein, an active component of Scutellaria baicalensis, protects against lipopolysaccharide-induced acute lung injury in rats. Journal of Ethnopharmacology, 153(1), 197-206.

Yun, B.A., Hwang, K.Y., Oh, J.W., Li, W., & Wang, C. (2020). Baicalin Inhibits TLR7/MYD88 Signaling Pathway Activation to Suppress Lung Inflammation in Mice Infected with Influenza A Virus. Microbiology and Immunology, 64(10), 714-722.

Zhang, Y., Li, X., Ciric, B., Ma, C.G., Gran, B., Rostami, A., & Zhang, G.X. (2015). Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway. Scientific Reports, 5, 17407.

Zhou, B.R., Zhang, L.C., Permatasari, F., Liu, J., Xu, Y., & Luo, D. (2014). ALA-PDT elicits oxidative damage and apoptosis in UVB-induced premature senescence of human skin fibroblasts. Photodiagnosis and Photodynamic Therapy, 11(2), 177-185.

QCT Technology

Arad, D., Kreisberg, R., & Shokhen, M. (1993). Structural and mechanical aspects of 3C proteases from the picornavirus family. Journal of Chemical Information and Computer Sciences, 33, 345–349.

Arad, D. (2002). The QCT technology for the design of novel protease inhibitors. Drug Design SMI Conference.

Arad, D., inventor; NLC Pharma Ltd, assignee. (2024). Compounds for treating coronavirus infection. United States patent US 11,857,517.

Bugg, T.D.H. (2001). The development of mechanistic enzymology in the 20th century. Natural Product Reports, 18, 465–493.

Halford, B. (2022). The Path to Paxlovid. ACS Central Science, 8, 405–407.

Koshland, D.E., Jr. (1995). The key–lock theory and the induced fit theory. Angewandte Chemie International Edition in English, 33, 2375–3278.

Pople, J.A., & Beveridge, D.L. (1970). Molecular orbital theory. New York: McGraw-Hill.

Shokhen, M., & Arad, D. (1996). The Source for the Difference Between Sulfhydryl and Hydroxyl Anions in Their Nucleophilic Addition Reaction to a Carbonyl Group: A DFT Approach. Journal of Molecular Modeling, 2, 399–409.

Development & Safety Studies

Cheng, Y.W., & Kuo, Y.H. (2013). Long-term systemic toxicity of shikonin derivatives in Wistar rats. Food and Chemical Toxicology, 58, 281-288.

Guo, C., He, J., Song, X., Tan, L., Wang, M., Jiang, P., Li, Y., Cao, Z., & Peng, C. (2019). Pharmacological properties and derivatives of shikonin—A review in recent years. Pharmacological Research, 149, 104463.

Jang, S.Y., Jeong, J.Y., & Seong, Y.H. (2015). Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats. Toxicological Research, 31(4), 403-410.

Jeong, D.H., & Jang, S.Y. (2015). Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs. Toxicological Research, 31(2), 159-166.

Kaeuffer, C., et al. (2020). Clinical characteristics and risk factors associated with severe COVID-19: Perspective analysis of 1,045 hospitalized cases in North-Eastern France, March 2020. NIH, 25(48).

Kim, S.J., & Kim, J.H. (2019). Sub-chronic oral toxicity of the aqueous extract of lithospermi radix in Fischer 344 rats. Food and Chemical Toxicology, 125, 570-579.

Li, C., Lin, G., & Zuo, Z. (2011). Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones. Biopharmaceutics & Drug Disposition, 32(8), 427-445.

Li, M., Wang, Y., Guo, R., Bai, Y., & Yu, Z. (2019). Glucuronidation of baicalin, baicalein and wogonin by human UGT1A9, 1A1, 1A3, 1A8 and 2B15. Xenobiotica, 49(7), 829-839.

Noh, K., Kang, Y., Nepal, M.R., Jeong, K.S., Oh, D.G., Kang, M.J., et al. (2016). Role of intestinal microbiota in baicalin-induced drug interaction and its pharmacokinetics. Molecules, 21(3), 337.

Oh, S.J., & Han, J.M. (2017). Assessment of the inhibition risk of shikonin on cytochrome P450 via cocktail inhibition assay. Drug Design, Development and Therapy, 11, 2927-2934.

Shi, L.L., Hao, J.J., Zhang, Y., Jiang, X.H., & Zhu, M. (2018). Mechanistic study on the intestinal absorption and disposition of baicalein. Biopharmaceutics & Drug Disposition, 39(1), 18-28.

Srinivas, N.R. (2010). Baicalin, an emerging multi-therapeutic agent: pharmacodynamics, pharmacokinetics, and considerations from drug development perspectives. Xenobiotica, 40(5), 357-367.

Wang, D.Y., & Zhang, M.N. (2020). Pharmacology, toxicity and pharmacokinetics of acetylshikonin: a review. Archives of Pharmacal Research, 43(11), 1255-1273.

Wang, Y., & Ge, W. (2016). Acetylshikonin from Zicao exerts antifertility effects at high dose in rats by suppressing the secretion of GTH. Phytomedicine, 23(13), 1631-1637.

Wu, H., Long, X., Yuan, F., Chen, L., Pan, S., Liu, Y., et al. (2014). Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound, baicalin. Acta Pharmaceutica Sinica B, 4(3), 217-226.

Yang, J.S., & Kim, H.S. (2008). Quantitative determination of acetylshikonin in macaque monkey blood by LC-ESI-MS/MS after precolumn derivatization with 2-mercaptoethanol and its application in pharmacokinetic study. Journal of Pharmaceutical and Biomedical Analysis, 48(3), 732-738.

Yune, T.Y., Lee, J.Y., Cui, C.M., Kim, H.C., & Oh, T.H. (2009). Neuroprotective effect of Scutellaria baicalensis on spinal cord injury in rats. Journal of Neurochemistry, 110(4), 1276-1287.

Zhang, L., Li, C., Lin, G., Krajcsi, P., & Zuo, Z. (2011). Hepatic metabolism and disposition of baicalein via the coupling of conjugation enzymes and transporters—in vitro and in vivo evidences. The AAPS Journal, 13(3), 378-389.