HMG-CoA reductase inhibitors: an updated review of biosynthesis and patent prospecting

Authors

DOI:

https://doi.org/10.33448/rsd-v11i14.36186

Keywords:

Statins; Fungi; Renewable substrates; Biopharmaceutical.

Abstract

HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the enzyme that plays a limiting role in cholesterol biosynthesis. Among the HMG-CoA reductase inhibitor molecules, statins stand out, a class of drug used in the treatment of atherosclerosis and in the reduction of high cholesterol levels, therefore they are biomolecules of medical and pharmaceutical importance. In this context, this work aimed to carry out a systematic mapping of patents and scientific articles related to the biosynthesis of HMG-CoA reductase inhibitors. The search was carried out in the databases of the National Institute of Intellectual Property (INPI), the European Patent Office (Espacenet), the Derwent Innovations Index, the World Intellectual Property Organization (WIPO) and also articles indexed in Scielo and Pubmed using as descriptors “statins”, “production and statins and fungi”, “statins and fungus”. Of the 2561 cataloged patents, 09 were included because they met the inclusion criteria. The number of scientific articles found in the databases was higher (2820) when compared to the number of patents. As a country, China represents the largest holder on the subject, corresponding to 88.9% of patented products. Based on the mapping, advances in the search for strategies for the biotechnological production of statins can be highlighted. Some of the inventions used microorganisms such as filamentous fungi associated with agro-industrial substrates as an alternative and low-cost source for the production of statins to replace synthetic sources. However, future studies can be carried out using new fungi and new renewable substrates, considering the existing biodiversity worldwide.

Author Biographies

Uiara Maria de Barros Lira Lins, Universidade Federal Rural de Pernambuco

DOCTORATE RENORBIO

Valberto Barbosa de Oliveira, Universidade Católica de Pernambuco

PCIAMB-UNICAP

Adriana Ferreira de Souza, Universidade Católica de Pernambuco

NPCIAMB-UNICAP

Dayana Montero Rodríguez, Universidade Federal de Pernambuco

NPCIAMB-UNICAP

Sérgio Selisman Silva Dantas, Universidade Católica de Pernambuco

NPCIAMB-UNICAP

Marcos Antônio Barbosa de Lima, Universidade Federal Rural de Pernambuco

Lab. UFRPE

Rosileide Fontenele da Silva Andrade, Universidade Católica de Pernambuco

NPCIAMB-UNICAP

References

Alizadehsani, R., Eskandarian, R., Behjati, M., Zahmatkesh, M., Roshanzamir, M., Izadi, N. H., ... & Islam, S. M. S. (2022). Factors associated with mortality in hospitalized cardiovascular disease patients infected with COVID‐19. Immunity, Inflammation and Disease, 10(3), e561.

Cedraz, I. S., & Lavorato, S. N. (2020). Fármacos utilizados no tratamento de hipercolesterolemia: uma análise histórica e químico-medicinal. Brazilian Journal of Health Review, 3(4), 8983-9004.

Chen L. (2019). Use of rice bran juice for the production of pravastatin by microbial fermentation, where the pravastatin production method involves inoculating activated Actinomadura mature into the culture medium, adding mevastatin to the medium to ferment the pravastatin. Patent CN108977469-A.

de Souza Menezes, J. D., de Souza, A. M., de Oliveira Fraga, V. T., & de Godoy, M. F. (2021). Fatores de risco em adultos jovens para o desenvolvimento de doenças cardiovasculares: o que a literatura mostra?. Research, Society and Development, 10(11), e492101119949-e492101119949.

Dikshit, R., & Tallapragada, P. (2016). Statistical optimization of lovastatin and confirmation of nonexistence of citrinin under solid-state fermentation by Monascus sanguineus. journal of food and drug analysis, 24(2), 433-440.

Feng X.; Zhang B.; Liu Y.; Chen Q.; iI F.; & Zhu Y. (2022). High-yield lovastatin red yeast rice as well as cultivation method and application thereof. Patent CN113881572 (A).

Gao L.; Jlixzhong X.; & Myao Z. (2021). Fermentation of lovastatin from red fermented rice by obtaining a fermentation product such as lovastatin from red fermented rice by inoculating fungal liquid of Monascus purpureus into a culture medium containing mainly rice for fermentation. Patent CN112779301(A).

Gholami-Shabani, M., Shams-Ghahfarokhi, M., Jamzivar, F., & Razzaghi-Abyaneh, M. (2022). Prospective Application of Aspergillus Species: Focus on Enzyme Production Strategies, Advances and Challenges.

Ram, H., Sen, K., Sakarwal, A., Charan, J., Sharma, P., Roy, R., & Ghosh, S. (2021). In-vitro and in-silico determinations of HMG-CoA reductase inhibition potential of caffeic acid for therapeutics of hypercholesterolemia. Journal of Applied Pharmaceutical Science, 12(1), 190-198.

González-Rivas, J. P., Nieto-Martínez, R., Brajkovich, I., Ugel, E., & Rísquez, A. (2018). Prevalence of dyslipidemias in three regions in Venezuela: the VEMSOLS study results. Arquivos Brasileiros de Cardiologia, 110, 30-35.

Sinha, R. P., & Häder, D. P. (2021). Natural Bioactive Compounds: Technological Advancements Chapter 13 – Biotechnological substances from fungi. Academic Press. P. 267-273.

Hasan, H., Abd Rahim, M. H., Campbell, L., Carter, D., Abbas, A., & Montoya, A. (2022). Increasing Lovastatin Production by Re-routing the Precursors Flow of Aspergillus terreus via Metabolic Engineering. Molecular Biotechnology, 64(1), 90-99.

Huang, J., Liao, N., & Li, H. (2018). Linoleic acid enhance the production of moncolin K and red pigments in Monascus ruber by activating mokH and mokA, and by accelerating cAMP-PkA pathway. International journal of biological macromolecules, 109, 950-954.

Jaivel, N., & Marimuthu, P. (2010). Optimization of lovastatin production in solid state fermentation by Aspergillus terreus. Int J Eng Sci Technol, 2(7), 2730-2733.

Javed, S., Meraj, M., Mahmood, S., Hameed, A., Naz, F., Hassan, S., & Irfan, R. (2017). Biosynthesis of lovastatin using agro-industrial wastes as carrier substrates. Tropical Journal of Pharmaceutical Research, 16(2), 263-269.

Jiang L.; Hzhang R.; Mzheng C. (2016). New Ac-32 strain of Aspergillus clavatus is useful in high-yield production of lovastatin. Patent CN105219653(A).

Jiang L.; Hzhang R.; & Xzheng L. (2016). New Aspergillus ninger Na-19 strain used to make lovastatin is preserved at the China Center for Type Culture Collection. Patent CN105602856-A.

Jiang L.; Jqian X; & Yyhan Z. (2017). New stain of Penicillium oxalicum is preserved at Canadian Clinical Trials Coordinating Centre, used to produce lovastatin. Patent CN106479900-A.

Jiang L.; Cshou L.; & Zzhang C. (2018). New Aspergillus versicolor Av-2 strain useful for the fermentative production of lovastatin. Patent CN108315265-A.

Kandil, O. (2004). The pharmaceutical industry in the Arab world: challenges, controversies, and future outlook. Drug discovery today, 9(13), 543-545.

Kashour, T., Halwani, R., Arabi, Y. M., Sohail, M. R., O’Horo, J. C., Badley, A. D., & Tleyjeh, I. M. (2021). Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility. Immunopharmacology and Immunotoxicology, 43(1), 37-50.

Martínez, M. M. L., Contreras, M. A., Marín, W., & D’Marco, L. (2020). Statins in COVID-19: is there any foundation?. Clínica e Investigación en Arteriosclerosis (English Edition), 32(6), 278-281.

Mahmoud, O. A., & Abdel_Hadi, S. Y. (2022). Extraction and Purification of Lovastatin from the Edible Mushroom Laetiporus sulphureus and its Antioxidant Activity. Egyptian Journal of Botany, 62(1), 169-175.

McLean, K. J., Hans, M., Meijrink, B., Van Scheppingen, W. B., Vollebregt, A., Tee, K. L., ... & Van Den Berg, M. A. (2015). Single-step fermentative production of the cholesterol-lowering drug pravastatin via reprogramming of Penicillium chrysogenum. Proceedings of the National Academy of Sciences, 112(9), 2847-2852.

Mihos, C. G., Pineda, A. M., & Santana, O. (2014). Cardiovascular effects of statins, beyond lipid-lowering properties. Pharmacological research, 88, 12-19.

Moreira, M. D., Melo, M. M., Coimbra, J. M., Dos Reis, K. C., Schwan, R. F., & Silva, C. F. (2018). Solid coffee waste as alternative to produce carotenoids with antioxidant and antimicrobial activities. Waste management, 82, 93-99.

Morofuji, Y., Nakagawa, S., Ujifuku, K., Fujimoto, T., Otsuka, K., Niwa, M., & Tsutsumi, K. (2022). Beyond lipid-lowering: effects of statins on cardiovascular and cerebrovascular diseases and cancer. Pharmaceuticals, 15(2), 151.

Mouafi, F. E., Ibrahim, G. S., & Elsoud, M. M. A. (2016). Optimization of lovastatin production from Aspergillus fumigatus. Journal of Genetic Engineering and Biotechnology, 14(2), 253-259.

Neto, R. N., Barros Gomes, E. D., Weba-Soares, L., Dias, L. R., da Silva, L. C., & de Miranda, R. D. (2019). Biotechnological Production of Statins: Metabolic Aspects and Genetic Approaches. Current pharmaceutical biotechnology, 20(15), 1244-1259.

Neto, P. D. S. G., Ferreira, J. M. S., de Matos Monteiro, P., Bandeira, M. G. A., & Nascimento, J. S. (2021). Praziquantel Associado a Alcaloide no Tratamento da Esquistossomose: prospecção tecnológica em uma perspectiva inovadora. Cadernos De Prospecção, 14(2), 489-489.

Pallem, C.; PparasA, G.; Manipati, S. (2018). Biosynthesis of Lovastatin, an Anti-cholesterol Drug by Aspergillus wentii NCIM 661 from Palm Kernel Cake via Solid-state Fermentation. Asian Journal of Biotechnology and Bioresource Technology, p. 1–7.

Prasanna Latha, D., & Hemalatha, K. P. J. (2015). Production of lovastatin by Aspergillus fischeri NCIM 509 using barley bran, wheat husk, rice bran and rice husk under solid state fermentation. Eur J Exp Biol, 5(8), 8-17.

Şahin, B., & İlgün, G. (2022). Risk factors of deaths related to cardiovascular diseases in World Health Organization (WHO) member countries. Health & Social Care in the Community, 30(1), 73-80.

SBC, Brazilian Society of Cardiology – Cardiovascular Diseases. Available in: <https://www.portal.cardiol.br>. Accessed on 25/02/2022.

Seenivasan, A., Venkatesan, S., & Tapobrata, P. (2018). Cellular localization and production of lovastatin from Monascus purpureus. Indian Journal of Pharmaceutical Sciences, 80(1), 85-98.

Simão, L., Wanderley, B. R. D. S. M., Nunes, I. L., & Fritzen-Freire, C. B. (2022). Prospecção Tecnológica de Patentes sobre Hidromel: panorama atual e perspectivas futuras. Cadernos de Prospecção, 15(3), 912-928.

Srinivasan, N., Thangavelu, K., & Uthandi, S. (2022). Lovastatin production by an oleaginous fungus, Aspergillus terreus KPR12 using sago processing wastewater (SWW). Microbial Cell Factories, 21(1), 1-14.

Subhan, M., Faryal, R., & Macreadie, I. (2016). Exploitation of Aspergillus terreus for the production of natural statins. Journal of Fungi, 2(2), 13.

Suwannarat, S. U. D. A. R. A. T., Iewkittayakorn, J. U. T. A. R. U. T., Sukpondma, Y. A. O. W. A. P. A., Rukachaisirikul, V., Phongpaichit, S., & Chotigeat, W. (2019). Optimization of the production of lovastatin from Aspergillus sclerotiorum PSU-RSPG178 under static liquid culture using response surface methodology. Sains Malays, 48(1), 93-102.

Tigre, P. B., & Kupfer, D. (2004). Prospecção Tecnológica. Rio de Janeiro: Senai, 2.

Who, World Health Organization – Cardiovascular Diseases.(s.d.). <https://www.paho.org/pt/topicos/doencas-cardiovasculares>.

Wu Z.; Hzhang L.; & Wzheng L. (2020). High yield lovastatin fungal fermentation method by preparing seed bottle culture medium, inoculating colony suspension, shake culture, preparing fermentation bottle culture medium, colony transplantation and shake culture. Patent CN111718970-A.

Xhuang Z.; Xyang L.; & Lteng C. (2020). The Aspergillus construct for the production of monacolin J by direct fermentation comprises the complete blockade of polyketide synthase lovf expression in Aspergillus. Patent WO2020038197(A1).

Xu X.; Dzheng C.; & Mwang Z. (2018). New Penicillium crustosum Pc-46 used for lovastatin fermentation production. Patent CN109182142 (A).

Downloads

Published

04/11/2022

How to Cite

LINS, U. M. de B. L. .; OLIVEIRA, V. B. de .; SOUZA, A. F. de .; RODRÍGUEZ, D. M. .; DANTAS, S. S. S.; LIMA, M. A. B. de; ANDRADE, R. F. da S. .; CAMPOS-TAKAKI, G. M. de. HMG-CoA reductase inhibitors: an updated review of biosynthesis and patent prospecting. Research, Society and Development, [S. l.], v. 11, n. 14, p. e508111436186, 2022. DOI: 10.33448/rsd-v11i14.36186. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/36186. Acesso em: 22 nov. 2024.

Issue

Section

Health Sciences