近十年天然产物药物的生物合成研究进展

doi:10.12211/2096-8280.2023-092

摘要/Abstract

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不足，庞大的陆地和海洋天然产物资源尚待开发。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

Abstract:

Natural products have long been considered as an important source for potential drugs. In history, natural products and their structural analogs have contributed substantially to the treatment of various diseases, especially cancers and infectious diseases. After a long history of applications, people have gradually begun to explore active ingredients in natural products that truly exert therapeutic effects, and discovered a series of functional compounds, such as morphine, quinine, ephedrine, etc. Over the past two hundred years, the discovery and research of natural products has undergone tremendous changes, from traditional identification and isolation methods to multidisciplinary approaches in the modern genomic era. Strategies for discovering natural products and tools for their prediction have been developed continuously. Although many novel and active natural products have been mined and discovered in the past two decades, considering the huge reserve of natural products in nature, a large number of genes or gene clusters encoding key enzymes for the biosynthesis of natural products have not yet been characterized, and both terrestrial and marine natural product resources are to be explored. Compared with traditional chemically synthesized molecules, natural products possess diverse skeletons for structural complexity, which have shown remarkable advantages in the discovery of new drugs. While there are still many challenges in discovering new drugs from natural products, such as the effective mining of molecules with new structural features, identification and isolation of functional natural products with trace abundance, derivatization of natural product analogs for exploring connections between their structures and activities, and the complete synthesis of complicated active natural products at large scales, etc., the emergence of novel analytical technologies and mining strategies is expected to substantially renovate natural product discovery. This review comments on the natural product drugs and semisynthetic drugs derived from natural products approved by the U.S. Food and Drug Administration within the past decade from January 2014 to October 2023, and provides an overview on the research progress on the biosynthesis of these natural products and their precursors. In addition, important progress in the biosynthesis of some drugs approved by FDA before is also briefly summarized. An in-depth understanding of the biosynthetic pathways and mechanisms underlying their efficacy is expected to provide valuable insights for the discovery and research of more new drugs in the future.

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

中图分类号:

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, 2024, 5(3): 408-446.

Jin FENG, Haixue PAN, Gongli TANG. Research advances in biosynthesis of natural product drugs within the past decade[J]. Synthetic Biology Journal, 2024, 5(3): 408-446.

图/表 24

表1 FDA批准的天然产物药物和半合成药物总结

Table 1 Summary of FDA-approved natural product drugs and semisynthetic drugs

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）^*	—	Ursusthibetanus	antiapoptotic	steroid	2022	Relyvrio	[23]
tapinarof^*	—	Photorhabdusluminescens	AhR agonist	polyketide	2022	Vtama	[24]
雌四醇（estetrol）^*	—	humans	hormone regulation	steroid	2021	Nextstellis	[25]
大麻二酚（cannabidiol）^*	—	Cannabissativa 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）^*	—	CandidatusEndoecteinascidiafrumentensis	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	Aspergillusdelacroxii	antifungal	non-ribosomal peptide	2023	Rezzayo	[31]
艾瑞芬净（ibrexafungerp）	enfumafungin	Hormonemacarpetanum	antifungal	terpene	2021	Brexafemme	[32]
伏环孢素（voclosporin）	cyclosporine	Beauverianivea	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	Artemisiaannua	antimalarial	terpene	2020	Artesunate	[35]
乳糖醇（lactitol）	lactose	animals	osmotic laxative	sugar alcohol	2020	Pizensy	[36]
来法莫林（lefamulin）^*	pleuromutilin	Clitopiluspasseckerianus	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	Amycolatopsisrifamycinica	antibacterial	polyketide	2018	Aemcolo	[39]
奥玛环素（omadacycline）	tetracyclines	Streptomyces	antibacterial	polyketide	2018	Nuzyra	[40]
普拉佐米星（plazomicin）	sisomicin	Micromonosporainositola	antibacterial	aminoglycoside	2018	Zemdri	[41]
莫昔克丁（Moxidectin）	avermectin	Streptomycesavermitilis	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	Streptomycesstaurosporeus	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	Amycolatopsisorientalis	antibacterial	glycopeptide	2014	Orbactiv	[49]
Earlier FDA-approved drugs:
奥利司他（orlistat）^*	lipstatin	Streptomycestoxytricini	lipase inhibitor	fatty acid	1999	Xenical	[50]
依托泊苷（etoposide）^*	podophyllotoxin	Podophyllumhexandrum	antitumor	lignan	1983	Vepesid	[51]
长春花碱（vinblastine）^*	—	Catharanthusroseus	antitumor	alkaloid	1965	Velban	[52]
长春新碱（vincristine）^*	—	Catharanthusroseus	antitumor	alkaloid	1963	Oncovin	[52]
秋水仙碱（colchicine）^*	—	Gloriosasuperba	anti-inflammatory	alkaloid	1961	Colbenemid	[53]
吗啡（morphine）^*	—	Papaversomniferum	analgesic	alkaloid	1941	Morphine sulfate	[54]
可待因（codeine）^*	—	Papaversomniferum	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）^*	—	Taxusbrevifolia	anticancer	terpene	1992	Taxol	[57]

表1 FDA批准的天然产物药物和半合成药物总结

Table 1 Summary of FDA-approved natural product drugs and semisynthetic drugs

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）^*	—	Ursusthibetanus	antiapoptotic	steroid	2022	Relyvrio	[23]
tapinarof^*	—	Photorhabdusluminescens	AhR agonist	polyketide	2022	Vtama	[24]
雌四醇（estetrol）^*	—	humans	hormone regulation	steroid	2021	Nextstellis	[25]
大麻二酚（cannabidiol）^*	—	Cannabissativa 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）^*	—	CandidatusEndoecteinascidiafrumentensis	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	Aspergillusdelacroxii	antifungal	non-ribosomal peptide	2023	Rezzayo	[31]
艾瑞芬净（ibrexafungerp）	enfumafungin	Hormonemacarpetanum	antifungal	terpene	2021	Brexafemme	[32]
伏环孢素（voclosporin）	cyclosporine	Beauverianivea	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	Artemisiaannua	antimalarial	terpene	2020	Artesunate	[35]
乳糖醇（lactitol）	lactose	animals	osmotic laxative	sugar alcohol	2020	Pizensy	[36]
来法莫林（lefamulin）^*	pleuromutilin	Clitopiluspasseckerianus	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	Amycolatopsisrifamycinica	antibacterial	polyketide	2018	Aemcolo	[39]
奥玛环素（omadacycline）	tetracyclines	Streptomyces	antibacterial	polyketide	2018	Nuzyra	[40]
普拉佐米星（plazomicin）	sisomicin	Micromonosporainositola	antibacterial	aminoglycoside	2018	Zemdri	[41]
莫昔克丁（Moxidectin）	avermectin	Streptomycesavermitilis	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	Streptomycesstaurosporeus	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	Amycolatopsisorientalis	antibacterial	glycopeptide	2014	Orbactiv	[49]
Earlier FDA-approved drugs:
奥利司他（orlistat）^*	lipstatin	Streptomycestoxytricini	lipase inhibitor	fatty acid	1999	Xenical	[50]
依托泊苷（etoposide）^*	podophyllotoxin	Podophyllumhexandrum	antitumor	lignan	1983	Vepesid	[51]
长春花碱（vinblastine）^*	—	Catharanthusroseus	antitumor	alkaloid	1965	Velban	[52]
长春新碱（vincristine）^*	—	Catharanthusroseus	antitumor	alkaloid	1963	Oncovin	[52]
秋水仙碱（colchicine）^*	—	Gloriosasuperba	anti-inflammatory	alkaloid	1961	Colbenemid	[53]
吗啡（morphine）^*	—	Papaversomniferum	analgesic	alkaloid	1941	Morphine sulfate	[54]
可待因（codeine）^*	—	Papaversomniferum	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）^*	—	Taxusbrevifolia	anticancer	terpene	1992	Taxol	[57]

图1 近十年FDA批准的天然产物药物及半合成药物的化学结构

Fig. 1 Chemical structures of natural products and semisynthetic drugs approved by FDA within the past decade

图2 近十年取得重要生物合成进展的FDA批准的老药的化学结构

Fig. 2 Chemical structures of drugs approved earlier by FDA and significant progress in their biosynthesis achieved within the past decade

图3 胆酸和去氧胆酸的生物合成CYP7A1—胆固醇7α-羟化酶；HSD3B7—3β-羟基-Δ5-C27-类固醇氧化还原酶；CYP8B1—12α-羟化酶；AKR1D1—Δ5-3-氧代类固醇5β-还原酶；AKR1C4—3α-羟基类固醇脱氢酶；CYP27A1—甾醇27-羟化酶；CH25H—甾醇25-羟化酶；CYP46A1—24β-羟化酶

Fig. 3 Biosynthesis of cholic and deoxycholic acidsCYP7A1—cholesterol 7α-hydroxylase; HSD3B7—3β-hydroxy-Δ5-C27-steroid oxidoreductase; CYP8B1—12α-hydroxylase; AKR1D1—Δ5-3-oxosteroid 5β-reductase; AKR1C4—3α-hydroxysteroid dehydrogenase; CYP27A1—sterol 27-hydroxylase; CH25H—sterol 25-hydroxylase; CYP46A1—24β-hydroxylase

图4 TUDCA在体内及体外的生物合成途径

Fig. 4 Biosynthetic pathways of TUDCA invivo and invitro

图5 从CDCA和LCA分别合成UDCA的体外生物转化

Fig. 5 Biotransformation of UDCA from CDCA and LCA invitro

图6 普拉睾酮和雌四醇在人体内的生物合成路径CYP11A1—细胞色素P450胆固醇侧链裂解酶；CYP17A1—17α-羟化酶/17，20-裂解酶；SULT2A1—磺基转移酶；STS—类固醇硫酸酯酶；AKR1C3—醛酮还原酶

Fig. 6 Biosynthetic pathways of prasterone and estetrol in humans CYP11A1—cytochrome P450 cholesterol side chain cleavage enzyme; CYP17A1—17α-hydroxylase/17,20-lyase; SULT2A1—sulfotransferase; STS—steroid sulfatase; AKR1C3—aldo/keto reductase

图7 二苯乙烯类天然产物在植物和发光杆菌中的生物合成途径C4H—肉桂酸-4-羟化酶；4CL—4-香豆酰-CoA连接酶；STS—二苯乙烯合酶；KS—酮基合酶；PAL—苯丙氨酸解氨酶

Fig. 7 Biosynthesis of stilbene natural products in plants and PhotorhabdusluminescensC4H—cinnamate-4-hydroxylase; 4CL—4-coumaroyl-CoA ligase; STS—stilbene synthase; KS—ketosynthase; PAL—phenylalanine ammonia-lyase

图8 StlD/StlC催化形成tapiranof的反应及StlD的酶催化机制

Fig. 8 Synthesis of tapiranof catalyzed by the enzyme StlD/StlC and the proposed catalytic mechanism for StlD

图9 大麻二酚及其他大麻素类似物的生物合成APT—芳香异戊烯基转移酶；CBDAS—大麻二酚酸合酶；THCAS—四氢大麻酚酸合酶；CBCAS—大麻色烯酸合酶；Δ9-THCA—Δ9-四氢大麻酚酸；CBCA—大麻色烯酸；Δ9-THC—Δ9-四氢大麻酚；CBC—大麻色原烯；PDAL—戊二乙酸内酯；HTAL—己酰三乙酸内酯；GPP—牻牛儿基焦磷酸

Fig. 9 Biosynthesis of CBD and other cannabinoid analoguesAPT—aromatic prenyltransferase; CBDAS—cannabidiolic acid synthase; THCAS—tetrahydrocannabinolic acid synthase; CBCAS—cannabichromenic acid synthase; Δ9-THCA—Δ9-tetrahydrocannabinolic acid; CBCA—cannabichromenic acid; Δ9-THC—Δ9-tetrahydrocannabinol; CBC—cannabichromene; PDAL—pentyl diacetic lactone; HTAL—hexanoyl triacetic acid lactone; GPP—geranyl pyrophosphate

图10 CBGA转化为CBDA和Δ9-THCA的不同的生物合成机制

Fig. 10 Different biosynthetic mechanisms for the conversion of CBGA to CBDA and Δ9-THCA

图11 CBGA在体外的酶法生物合成AckA—乙酸激酶；PTA—磷酸乙酰基转移酶；MdcA—丙二酸脱羧酶；MatB—丙二酰辅酶A合成酶；ADK—腺苷酸激酶；AAE3—酰基激活酶；ThiM—羟乙基噻唑激酶；IPK—磷酸激酶；GPPS—牻牛儿基焦磷酸合酶

Fig. 11 Enzymatic biosynthesis of CBGA invitroAckA—acetate kinase; PTA—phosphate acetyltransferase; MdcA—malonate decarboxylase; MatB—malonyl-CoA synthetase; ADK—adenylate kinase; AAE3—acyl-activating enzyme; ThiM—hydroxyethylthiazole kinase; IPK—phosphate kinase; GPPS—geranyl pyrophosphate synthase

图12 奥利司他化学结构及推测的利普司他汀生物合成途径C—缩合结构域；A—腺苷化结构域；T—硫酯化结构域

Fig. 12 Chemical structure of orlistat and proposed biosynthetic pathway of lipstatinC—condensation domain; A—adenylation domain; T—thiolation domain

图13 推测的LstAB非脱羧缩合机制

Fig. 13 Proposed mechanism for the nondecarboxylating condensation catalyzed by LstAB

图14 推测的ET-743生物合成途径AL—酰基辅酶A连接酶结构域；TR—末端还原酶结构域

Fig. 14 Proposed biosynthetic pathway of ET-743AL—acyl-CoA ligase domain; TR—terminal reductase domain

图15 推测的棘白菌素B生物合成途径

Fig. 15 Proposed biosynthetic pathway of echinocandin B

图16 依托泊苷苷元的生物合成途径（蓝色为新表征的酶）DIR—定向蛋白；PLR—松脂醇-落叶松脂醇还原酶；SDH—开环异落叶松脂酚脱氢酶；CYP719A23/71CU1/71BE54/82D61—细胞色素P450；OMT1/3—O-甲基转移酶；2-ODD—2-酮戊二酸/Fe（Ⅱ）依赖双加氧酶

Fig. 16 Biosynthetic pathway of etoposide aglycone(Newly characterized enzymes are highlighted in blue) DIR—dirigent protein; PLR—pinoresinol-lariciresinol reductase; SDH—secoisolariciresinol dehydrogenase; CYP719A23/71CU1/71BE54/82D61—cytochromes P450; OMT1/3—O-methyltransferases; 2-ODD—2-oxoglutarate/Fe(Ⅱ)-dependent dioxygenase

图17 长春花碱和长春新碱的生物合成途径（蓝色为新表征的酶）

Fig. 17 Biosynthetic pathway of vinblastine and vincristine(Newly characterized enzymes are highlighted in blue)

图18 秋水仙碱的生物合成途径（蓝色为新表征的酶）OMT1/2/3/4—O-甲基转移酶；NMT—N-甲基转移酶；CYP75A109/75A110/71FB1—细胞色素P450

Fig. 18 Biosynthetic pathway of colchicine(Newly characterized enzymes are highlighted in blue) OMT1/2/3/4—O-methyltransferases; NMT—N-methyltransferase; CYP75A109/75A110/71FB1—cytochromes P450

图19 吗啡和可待因的生物合成途径（蓝色为新表征的酶）

Fig. 19 Biosynthetic pathway of morphine and codeine(Newly characterized enzymes are highlighted in blue)

图20 东莨菪碱的生物合成途径（蓝色为新表征的酶）

Fig. 20 Biosynthetic pathway of scopolamine(Newly characterized enzymes are highlighted in blue)

图21 二萜类天然产物截短侧耳素的生物合成途径

Fig. 21 Biosynthetic pathway of the diterpene natural product pleuromutilin

图22 血管紧张素Ⅱ在人体内的生物合成

Fig. 22 Biosynthesis of angiotensin Ⅱ in humans

图23 近十年新发现的涉及生物合成且有发展为抗生素药物潜力的代表性天然产物

Fig. 23 Representative natural products biosynthesied within the past decade with potentials for being developed as antibiotics

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