Research advances in biosynthesis of natural product drugs in the past decade

doi:10.12211/2096-8280.2023-092

Abstract

Abstract:

Natural products have long been considered as an important source of potential lead drugs. In history, natural products and their structural analogs have made enormous contributions to the treatment of diseases, especially the treatment of cancer and infectious diseases. After a long application history, people gradually began to explore the active ingredients in natural products that truly exert therapeutic effects, and discovered a series of classic natural products, such as morphine, quinine, ephedrine, etc. Especially over the past two hundred years, the discovery and research of natural products has tremendously undergone changes and developments, transitioning from traditional isolation and identification methods to multidisciplinary approaches in the modern genomic era. An increasing number of natural product discovery strategies and genomic prediction tools have been developed. Although many novel and active natural products have been continuously discovered and mined in the past two decades, considering the total amount of natural products in nature, a substantial number of natural product biosynthetic gene clusters have not yet been characterized, and there are still vast terrestrial and marine natural product resources to be explored. Compared with traditional chemically synthesized molecules, natural products possess abundant skeleton diversity and structural complexity, which have shown remarkable advantages in new drug discovery. While there are still various challenges in the innovation of new drugs based on natural products, such as the effective mining of molecules with new structural features, isolation and identification of trace amounts of natural products, derivatization of natural product analogs for exploring structure-activity relationships, and industrial total synthesis of complex active natural products, etc., the emergence of novel analytical technologies and mining strategies is expected to usher in a new stage of natural product discovery. This review consolidates information on the natural product drugs and semisynthetic drugs derived from natural products approved by the U.S. Food and Drug Administration in the past decade (January 2014 to October 2023), and provides an overview on the research progress on biosynthesis of these natural products and semisynthetic drug precursors. In addition, important biosynthetic progress in some old FDA-approved drugs over the past decade is briefly summarized. The in-depth understanding of the biosynthetic pathways and mechanisms of these drug-related natural products is expected to provide valuable insights for the discovery and research of more innovative drugs in the future.

Key words: natural products, semisynthetic drugs, drug discovery, biosynthesis

摘要：

天然产物一直是潜在的先导药物的重要来源，天然产物及其结构类似物在历史上对疾病治疗做出了重大贡献，特别是对癌症和传染病的治疗。在过去两百年的时间里，天然产物的发现和研究经历了巨大的变化，由传统的分离鉴定为主的经典研究方法转为了基因组时代的多学科组合研究。虽然近二十年发现和挖掘了丰富的活性天然产物，但与自然界中巨大的天然产物合成潜力相比，仍有庞大的陆地和海洋天然产物资源有待开发。同时，与传统的化学合成分子相比，天然产物具有丰富的骨架多样性和结构复杂性，在新药发现中展现了巨大的优势。虽然在天然产物的新药创新方面仍面临着种种挑战，但新的分析技术和挖掘策略的出现有望迎来天然产物发现的新阶段。本文总结了近十年（2014年1月-2023年10月）美国食品药品监督管理局批准成药的天然产物及源自天然产物的半合成药物，并对其中纯天然产物来源分子、重要的半合成天然产物前体的生物合成研究进展进行了详细总结。此外还简要总结了一些FDA批准的老药在过去十年中取得的重要生物合成研究进展。期望通过对成药天然产物生物合成途径及机制的深入理解，为更多天然产物创新药物的发现和研究提供借鉴。

关键词: 天然产物, 半合成药物, 新药发现, 生物合成

CLC Number:

Jin FENG, Haixue PAN, Gongli TANG. Research advances in biosynthesis of natural product drugs in the past decade[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2023-092.

冯金, 潘海学, 唐功利. 近十年天然产物药物的生物合成研究进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2023-092.

Figures/Tables 24

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批准药物	药物前体	来源	主要功效	结构类型	批准时间	商品名	参考文献
Natural product drugs:
牛磺酸二醇（Taurursodiol）^*	-	Ursus thibetanus	Antiapoptotic	Steroid	2022	Relyvrio	[23]
Tapinarof^*	-	Photorhabdus luminescens	AhR agonist	Polyketide	2022	Vtama	[24]
雌四醇（Estetrol）^*	-	Humans	Hormone regulation	Steroid	2021	Nextstellis	[25]
大麻二酚（Cannabidiol）^*	-	Cannabis sativa L.	Analgesic, anticonvulsant	Polyketide	2018	Epidiolex	[26]
血管紧张素（Angiotensin）II^*	-	Humans	Blood pressure regulation	Peptide	2017	Giapreza	[27]
普拉睾酮（Prasterone）^*	-	Humans	Hormone regulation	Steroid	2016	Intrarosa	[28]
曲贝替定（Trabectedin）^*	-	CandidatusEndoecteinascidia frumentensis	Antitumor	Non-ribosomal peptide	2015	Yondelis	[29]
胆酸（Cholic acid）^*	-	Animals	Facilitating fat absorption	Steroid	2015	Cholbam	[30]
去氧胆酸（Deoxycholic acid）^*	-	Animals	Cytolytic agent	Steroid	2015	Kybella	[30]
Semisynthetic drugs:
瑞扎芬净（Rezafungin）^*	Echinocandin	Aspergillus delacroxii	Antifungal	Non-ribosomal peptide	2023	Rezzayo	[31]
艾瑞芬净（Ibrexafungerp）	Enfumafungin	Hormonema carpetanum	Antifungal	Terpene	2021	Brexafemme	[32]
伏环孢素（Voclosporin）	Cyclosporine	Beauveria nivea	Calcineurin inhibitor	Non-ribosomal peptide	2021	Lupkynis	[33]
克拉司酮（Clascoterone）	Progesterone	Humans	Topical androgen antagonist	Steroid	2020	Winlevi	[34]
青蒿琥酯（Artesunate）	Artemisinin	Artemisia annua	Antimalarial	Terpene	2020	Artesunate	[35]
乳糖醇（Lactitol）	Lactose	Animals	Osmotic laxative	Sugar alcohol	2020	Pizensy	[36]
来法莫林（Lefamulin）^*	Pleuromutilin	Clitopilus passeckerianus	Antibacterial	Terpene	2019	Xenleta	[37]
布瑞诺龙（Brexanolone）	Pregnanolone	Humans	Antidepressant	Steroid	2019	Zulresso	[38]
利福霉素（Rifamycin）SV	Rifamycin B	Amycolatopsis rifamycinica	Antibacterial	Polyketide	2018	Aemcolo	[39]
奥玛环素（Omadacycline）	Tetracyclines	Streptomyces	Antibacterial	Polyketide	2018	Nuzyra	[40]
普拉佐米星（Plazomicin）	Sisomicin	Micromonospora inositola	Antibacterial	Aminoglycoside	2018	Zemdri	[41]
莫昔克丁（Moxidectin）	Avermectin	Streptomyces avermitilis	Antiparasitic	Polyketide	2018	Moxidectin	[42]
艾拉环素（Eravacycline）	Tetracyclines	Streptomyces	Antibacterial	Polyketide	2018	Xerava	[43]
萨瑞环素（Sarecycline）	Tetracyclines	Streptomyces	Antibacterial	Polyketide	2018	Seysara	[44]
米哚妥林（Midostaurin）	Staurosporine	Streptomyces staurosporeus	Antineoplastic	Alkaloid	2017	Rydapt	[45]
奥贝胆酸（Obeticholic acid）	Cholic acid	Animals	FXR agonist	Steroid	2016	Ocaliva	[46]
尿苷三乙酸酯（Uridine triacetate）	Uridine	Animals	Antidote	Nucleoside	2015	Xuriden	[47]
头孢洛扎（Ceftolozane）	Cephalosporin	Acremonium	Antibacterial	Beta-lactam	2014	Zerbaxa	[48]
奥利万星（Oritavancin）	Chloroeremomycin	Amycolatopsis orientalis	Antibacterial	Glycopeptide	2014	Orbactiv	[49]
Earlier FDA-approved drugs:
奥利司他（Orlistat）^*	Lipstatin	Streptomyces toxytricini	Lipase inhibitor	Fatty acid	1999	Xenical	[50]
依托泊苷（Etoposide）^*	Podophyllotoxin	Podophyllum hexandrum	Antitumor	Lignan	1983	Vepesid	[51]
长春花碱（Vinblastine）^*	-	Catharanthus roseus	Antitumor	Alkaloid	1965	Velban	[52]
长春新碱（Vincristine）^*	-	Catharanthus roseus	Antitumor	Alkaloid	1963	Oncovin	[52]
秋水仙碱（Colchicine）^*	-	Gloriosa superba	Anti-inflammatory	Alkaloid	1961	Colbenemid	[53]
吗啡（Morphine）^*	-	Papaver somniferum	Analgesic	Alkaloid	1941	Morphine sulfate	[54]
可待因（Codeine）^*	-	Papaver somniferum	Analgesic	Alkaloid	1950	Codeine sulfate	[54]
东莨菪碱（Scopolamine）^*	-	Solanaceae	Anticholinergic	Alkaloid	1979	Transderm Scop	[55]
维生素（Vitamin）B₁₂^*	-	Archaea, bacteria	Supplement	Alkaloid	1942	Cyanocobalamin	[56]
紫杉醇（Paclitaxel）^*	-	Taxus brevifolia	Anticancer	Terpene	1992	Taxol	[57]

批准药物	药物前体	来源	主要功效	结构类型	批准时间	商品名	参考文献
Natural product drugs:
牛磺酸二醇（Taurursodiol）^*	-	Ursus thibetanus	Antiapoptotic	Steroid	2022	Relyvrio	[23]
Tapinarof^*	-	Photorhabdus luminescens	AhR agonist	Polyketide	2022	Vtama	[24]
雌四醇（Estetrol）^*	-	Humans	Hormone regulation	Steroid	2021	Nextstellis	[25]
大麻二酚（Cannabidiol）^*	-	Cannabis sativa L.	Analgesic, anticonvulsant	Polyketide	2018	Epidiolex	[26]
血管紧张素（Angiotensin）II^*	-	Humans	Blood pressure regulation	Peptide	2017	Giapreza	[27]
普拉睾酮（Prasterone）^*	-	Humans	Hormone regulation	Steroid	2016	Intrarosa	[28]
曲贝替定（Trabectedin）^*	-	CandidatusEndoecteinascidia frumentensis	Antitumor	Non-ribosomal peptide	2015	Yondelis	[29]
胆酸（Cholic acid）^*	-	Animals	Facilitating fat absorption	Steroid	2015	Cholbam	[30]
去氧胆酸（Deoxycholic acid）^*	-	Animals	Cytolytic agent	Steroid	2015	Kybella	[30]
Semisynthetic drugs:
瑞扎芬净（Rezafungin）^*	Echinocandin	Aspergillus delacroxii	Antifungal	Non-ribosomal peptide	2023	Rezzayo	[31]
艾瑞芬净（Ibrexafungerp）	Enfumafungin	Hormonema carpetanum	Antifungal	Terpene	2021	Brexafemme	[32]
伏环孢素（Voclosporin）	Cyclosporine	Beauveria nivea	Calcineurin inhibitor	Non-ribosomal peptide	2021	Lupkynis	[33]
克拉司酮（Clascoterone）	Progesterone	Humans	Topical androgen antagonist	Steroid	2020	Winlevi	[34]
青蒿琥酯（Artesunate）	Artemisinin	Artemisia annua	Antimalarial	Terpene	2020	Artesunate	[35]
乳糖醇（Lactitol）	Lactose	Animals	Osmotic laxative	Sugar alcohol	2020	Pizensy	[36]
来法莫林（Lefamulin）^*	Pleuromutilin	Clitopilus passeckerianus	Antibacterial	Terpene	2019	Xenleta	[37]
布瑞诺龙（Brexanolone）	Pregnanolone	Humans	Antidepressant	Steroid	2019	Zulresso	[38]
利福霉素（Rifamycin）SV	Rifamycin B	Amycolatopsis rifamycinica	Antibacterial	Polyketide	2018	Aemcolo	[39]
奥玛环素（Omadacycline）	Tetracyclines	Streptomyces	Antibacterial	Polyketide	2018	Nuzyra	[40]
普拉佐米星（Plazomicin）	Sisomicin	Micromonospora inositola	Antibacterial	Aminoglycoside	2018	Zemdri	[41]
莫昔克丁（Moxidectin）	Avermectin	Streptomyces avermitilis	Antiparasitic	Polyketide	2018	Moxidectin	[42]
艾拉环素（Eravacycline）	Tetracyclines	Streptomyces	Antibacterial	Polyketide	2018	Xerava	[43]
萨瑞环素（Sarecycline）	Tetracyclines	Streptomyces	Antibacterial	Polyketide	2018	Seysara	[44]
米哚妥林（Midostaurin）	Staurosporine	Streptomyces staurosporeus	Antineoplastic	Alkaloid	2017	Rydapt	[45]
奥贝胆酸（Obeticholic acid）	Cholic acid	Animals	FXR agonist	Steroid	2016	Ocaliva	[46]
尿苷三乙酸酯（Uridine triacetate）	Uridine	Animals	Antidote	Nucleoside	2015	Xuriden	[47]
头孢洛扎（Ceftolozane）	Cephalosporin	Acremonium	Antibacterial	Beta-lactam	2014	Zerbaxa	[48]
奥利万星（Oritavancin）	Chloroeremomycin	Amycolatopsis orientalis	Antibacterial	Glycopeptide	2014	Orbactiv	[49]
Earlier FDA-approved drugs:
奥利司他（Orlistat）^*	Lipstatin	Streptomyces toxytricini	Lipase inhibitor	Fatty acid	1999	Xenical	[50]
依托泊苷（Etoposide）^*	Podophyllotoxin	Podophyllum hexandrum	Antitumor	Lignan	1983	Vepesid	[51]
长春花碱（Vinblastine）^*	-	Catharanthus roseus	Antitumor	Alkaloid	1965	Velban	[52]
长春新碱（Vincristine）^*	-	Catharanthus roseus	Antitumor	Alkaloid	1963	Oncovin	[52]
秋水仙碱（Colchicine）^*	-	Gloriosa superba	Anti-inflammatory	Alkaloid	1961	Colbenemid	[53]
吗啡（Morphine）^*	-	Papaver somniferum	Analgesic	Alkaloid	1941	Morphine sulfate	[54]
可待因（Codeine）^*	-	Papaver somniferum	Analgesic	Alkaloid	1950	Codeine sulfate	[54]
东莨菪碱（Scopolamine）^*	-	Solanaceae	Anticholinergic	Alkaloid	1979	Transderm Scop	[55]
维生素（Vitamin）B₁₂^*	-	Archaea, bacteria	Supplement	Alkaloid	1942	Cyanocobalamin	[56]
紫杉醇（Paclitaxel）^*	-	Taxus brevifolia	Anticancer	Terpene	1992	Taxol	[57]

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