Are we seeing a resurgence in the use of natural products for new drug discovery?

1. Introduction

The contribution of natural products (NPs) to drug development has been extensively documented. The structural diversity and biological activity of NPs make them the most valuable sources of drugs and drug leads. Table 1 shows examples of representative drugs discovered from NPs. They include several well-known history-changing drugs, such as penicillin, morphine, paclitaxel, avermectins, and artemisinin. In fact, more than one-third of all the US FDA-approved therapeutic agents over the past 20 years are derived from or inspired by NPs, and more than 50% of the developed small-molecule drugs from 1981 to 2014 were originated from NPs, semi-synthetic NPs and NP-derived mimetics [1]. Since cytarabine became the first FDA-approved marine-derived anticancer drug in 1969, exploitation of marine environments especially marine microorganisms has led to encouraging outcomes. So far, more than 28,500 marine natural products (MRPs) have been identified, in a rate of ~1000 new compounds per year since 2008, including approximately 1490 new compounds in 2017 [2]. Many of these MRPs have been applied in medicine and agrochemistry, such as the commercialized Cytarabine, Vidarabine, Eribulin, and Ziconotide. These results demonstrate that MRPs might be the most recent source of bioactive molecules, and their potentials as novel drugs or drug leads are underexplored. The climax of the story emerged in 2015, when the Nobel Prize in Physiology or Medicine was awarded to William C. Campbell and Satoshi Omura, and Youyou Tu for the discovery of avermectins and artemisinin, respectively.

Table 1. Examples of representative drug discoveries from natural products.

Category	Natural products	Sources	Medicinal purposes
Plants	Morphine	Papaver somniferum L.	Analgesic
	Salicin	Salix alba L.	Analgesic
	Paclitaxel	Taxus brevifolia Nutt.	Antineoplastic
	Anisodamine	Anisodus tanguticus (Maxim.) Pascher	Anticholinergic
	Aescin	Aesculus hippocastanum L.	Anti-inflammatory
	Berberine	Berberis vulgaris L.	Bacillary dysentery
	Theophylline	Camellia sinensis (L.) Kuntze	Diuretic & bronchodilator
	Cocaine	Erythroxylum coca Lamk.	Local anaesthetic
	Digitoxin	Digitalis purpurea L.	Cardiotonic
	Andrographolide	Andrographis paniculata Nees	Bacillary dysentery
	Artemisinin	Artemisia annua L.	Antimalarial
	Quinine	Cinchona ledgeriana Moens ex. Trimen	Antimalarial
	Vincristine	Catharanthus roseus (L.) G. Don	Antineoplastic
	Galantamine	Lycoris squamigera Maxim	Treatment of cognitive decline
	Pilocarpine	Pilocarpus jaborandi Holmes	Treatment of dry mouth, glaucoma
	Apomorphine	Papaver somniferum L.	Antiparkinsonism
	Tubocurarine	Chondrodendron tomentosum	Muscle relaxant
Microorganisms	Penicillin	Penicillium notatum	Antibiotic
	Tetracycline	Streptomyces aureofaciens	Antibiotic
	Doxorubicin	Streptomyces peucetius	Anticancer
	Cyclosporine	Tolypocladium inflatum	Immunosuppressant
	Norcardicins	Nocardia uniformis subsp.	Antibiotic
	Imipenem	Streptomyces cattleya	Antimicrobial
	Aztreonam	Chromobacterium violaceum	Antibiotic
	Vancomycin	Amycolatopsis orientalis	Antibiotic
	Erythromycin	Saccharopolyspora erythraea	Antibacterial
	Mevastatin	Penicillium citrinum	Cholesterol-lowering
Marine organisms	Cytarabine (ara-C)	Cryptotheca crypta	Anticancer
	Vidarabine (ara-A)	Cryptotethya crypta	Antiviral
	Ziconotide (Prialt)	Conus magus	Analgesic
	Ecteinascidin 743	Ecteinascidia turbinata	Anticancer
	Eribulin mesylate	Halichondria okadai	Antitumor
	Brentuximab vedotin	Dolabella auricularia	Anticancer

2. History of drug discovery with NPs

Figure 1 illustrates a brief timeline of selected milestones of drug discovery from NPs. In ancient time, plant-based drugs rich in bioactive NPs were used in the forms of oils, infusions, and pills to treat colds, coughs and other diseases. The oldest recorded text for the use of NPs as a therapeutic agent was in Mesopotamia around 2600 BC [3]. However, the use of these natural medicinal plant products is mainly based on human experimentation by trial-and-error for hundreds of centuries through palatability trials or untimely deaths and searching for available foods for the treatment of diseases [4]. There are several milestones throughout the history of NP-based drug discovery. It is perceived as the start of the Golden Age of NP-based drug discovery following the discovery of penicillin by Alexander Fleming and Howard Florey, as well as the discovery of streptomycin by Selman A. Waksman (Figure 1). Soon after the landmark discovery of penicillin G, came tetracycline from Streptomyces aureofaciens, doxorubicin from Streptomyces peucetius, and other classes of antibiotic microbial NPs which were discovered one after another. In the pre-genomic era, most efforts on NP-based drug discovery were put in a ‘top-down’ approach initiated by a screening of biological samples for desirable bioactivities, followed by the compounds’ isolation and characterization [5]. By the 1990s, such strategies were gradually discouraged because of the rediscovery of known compounds, the technical barriers to the isolation of compounds from extracts and the incompatibility to high-throughput screening (HTS) platforms. Major pharmaceutical companies diminished or even terminated their NPs programs and shifted their focus to target-based drug discovery which relies on HTS of synthetic chemical libraries. Unlike phenotype screens, target-based approaches are based on the validated understanding of the interaction of tested compounds with the designated targets and thus are considered to have higher hitting rates. Unfortunately, this strategic shift correlated with the overall reduction in novel lead compounds in the drug development pipeline and the substantial decline in new drug approval [6]. The lack of the structural diversity and complexity given by nature to NPs is one of the main drawbacks of combinatorial libraries [7]. Results from some large screening collections suggest the diversity within biologically relevant ‘chemical space’ might be more important than library size [8]. Thus, the diversity-oriented synthesis approach and the selection of plates containing NPs were used in HTS campaigns to improve the hitting rates [9]. Recent advances in analytical and computational techniques provide powerful tools for processing complex NPs and developing novel drugs based on their structures [10].

Figure 1. A brief timeline of selected milestones of drug discovery from natural products.

3. Challenges in NP-based research and drug development

Although NPs play a pivotal role in innovative drug discovery, there are some challenges of finding NP-based drug candidates that can treat various communicable and non-communicable diseases with no or little side effects. First, the majority of natural lead compounds has no or low druggability [11]. While some NPs possess bioactivity or drug-like activity [12], many NPs have poor solubility or chemical instability, severely hindering their transformation to parenteral drugs. Moreover, the complex structures of many NPs give them high molecular weights, which will most likely impose negative effects on the intestinal absorption [11]. Therefore, these structural phenotypes have to be subjected to selective modification with the purposes of improving physicochemical properties, increasing the chemical and metabolic stability, enhancing pharmacokinetic characteristics, and minimizing side-effects [13].

Secondly, despite the advances in technology and analytical instruments over the past decades [8], the low hitting rate of novel drug discovery with NPs is still a major issue. In general, two different complementary approaches have been used for drug discovery: phenotypic screening and target-based approaches. The use of traditional NP screening approaches was gradually diminished due to the repeated isolation of known compounds, technological difficulties, and increased cost. NP libraries are also considered to be incompatible with HTS platforms [14]. In general, HTS requires high accuracy, reproducibility, robustness and reliable liquid handling systems. However, many NPs often do not meet these requirements. More details on the challenges of NP samples for HTS are referred to the reviews by Henrich and Beutler [15]. Target-based discovery, which relies on the scientific advances in the fields of chemistry, biochemistry, genomics, and technology, shows advantages over traditional NPs screening. However, it is noteworthy that the first-in-class small-molecule drugs discovered by phenotypic screening were comparable to or even more than those by target-based approaches over the past 15 years [16].

Thirdly, the pharmaceutical industry heavily depends on protected NPs patents. However, the intellectual property of original (unmodified) NPs is often less clear. Limitations to a patent directed to NPs have been challenged in terms of patent eligibility. In 2014, the US Patent and Trademark Office (USPTO) issued the Guidance for Determining Subject Matter Eligibility of Claims Reciting or Involving Laws of Nature, Natural Phenomena, & Natural Products based on Mayo Myriad Supreme Court decisions. An essential prerequisite for a patent claim is to show distinguished difference from a known natural law, material or phenomenon. Therefore, this guidance might impose a significant effect on how to protect a product type invention directed to NPs. Predictably, despite lots of efforts on isolation, purification or synthetic process of NPs, it is now more difficult than before for companies to patent NPs that are not fundamentally different from known NPs [17]. Therefore, when one prepares a patent to cover NPs, one must think over how different it is between the products to be patented and those NPs for effective intellectual property protection to exclude generic drug companies. To achieve this goal, it is of significance to prepare a well-designed patent strategy in advance of the actual research and development. Modifying NPs might be one important approach to gain intellectual property. In order to match the above challenges in NP-based drug discovery, researchers should increase their consideration in natural product chemistry, screening, use, and development.

4. Conclusion

The use and exploitation of bioactive substances exist throughout the history of mankind. The versatile roles of NPs in treating human diseases have been extensively documented in the past. Although there are identified challenges to be met in NP-based drug discovery and development, we have seen a resurgence recently in the use of NPs for new drug discovery, which thanks for application of new cutting-edge technologies.

Further, we expect that the use of NPs will be further increased for the purpose of new drug discovery and development in the near future. NPs will continue to be a major source of novel lead compounds or pharmacophores for medicinal chemistry due to their structural diversity and wide-ranged biological activities; however maybe only a very small portion of this ‘gold mine’ had just been discovered, exploited and used by mankind. Both phenotypic screening and target-based screening strategies play their important roles in the discovery of some history-changing drugs that greatly affect human life. Innovative drug discovery strategies will be of significance in meeting global public health challenges. The challenges associated with NP-based research and drug development have been identified and need to be addressed. Advances in bioinformatics, structural biology, proteomics, genomics and metagenomics, and analytical technologies will open up opportunities for future drug discovery from complex NPs. Also, in the future, with continuing insights into the understanding of the molecular basis of various human diseases, more smart and high efficient screening approaches will be developed for NP-based drug discovery.

5. Expert opinion

Despite great progress made in discovering drugs to treat various diseases in the past decades, the scourge of communicable and non-communicable diseases will continue to be a huge challenge for global public health. Thus, finding effective candidate drugs that can protect patients from these diseases is an indispensable mission for the pharmaceutical industry and academia. NPs provide an endless treasure trove of biomaterials to help in searching for and designing pharmacologically important new, novel, lead drugs.

Historically, various NP-derived medicines (especially those from plant origin) have been widely used to prevent and/or treat many pathological conditions, despite the lack of elucidation of pharmacological mechanisms and documented clinical trials. Furthermore, these herbal medicines are used mainly in the form of concentrated plant extracts consisting of many different ingredients. By contrast, current drug discovery strategies and modern medicine have changed the practice in traditional medicine, requiring the isolation of one or two active components with high purity in order to be used for treating diseases. However, as revealed in many cellular and animal experiments, therapeutic efficacies of the isolated active compounds when used individually are not as satisfactory as those of original plant extracts, suggesting that the most of these plant metabolites exert their pharmacological effects in a synergistic fashion or concurrently. The use of natural medicinal plants has shown an increasing trend worldwide in the past decades. For example, in 2011, Germany approved for the first time the clinical use of a cannabis extract to treat moderate to severe refractory spasticity in multiple sclerosis [18]. Considering the pathological complexity of many diseases e.g., cancer and degenerative disorders, treatment with a single compound might not achieve satisfactory therapeutic effects. Therefore, it is important for future drug discovery to consider potential synergistic actions of different ingredients in a natural product. More attention should also be given to the use of whole plant extracts instead of single isolated compounds in research to understand mechanisms of action of medical plant extracts. Treatment design or strategy should also consider a combinational approach, where multiple chemotherapeutic agents either target the same pathway or work synergistically may be used in combination [1].

More attention should be paid to innovative drug discovery strategies. As we all know, the discovery of many blockbuster drugs, derived directly from NPs or NP-inspired derivatives, benefits from the advances in technological and analytical instruments [19]. In the past 25 years, technological advances in genomics have contributed to the rapid identification and interpretation of genetic differences driving patient-specific features of the disease, which may lay the foundations for the development of precision medicine. Advances in multiple fields (bioinformatics, proteomics, genomics, metagenomics, and analytical technologies) have generated and will continue to open up new opportunities for NP-based drug discovery. In fact, these technological innovations have radically expanded the NPs chemical space and shown the feasibility of engineered NPs production from uncultivated species or species on the verge of extinction in model heterologous hosts. Furthermore, the use of organ-on chips, microfluidics technology, and Artificial Intelligence will definitely enhance drug design hypotheses, accelerate the speed in the assessment of the safety, pharmacokinetics and efficacy of candidate compounds, and improve the success rate of hitting some new therapeutic moieties [10]. All the above, plus rapidly developing computational will definitely play an essential role in the development of next-generation drugs to combat the health challenges of today and the future.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Jean Guerin and Rania Fardous for critical reading of the manuscript.

Additional information

Funding

The authors were supported by the National Natural Science Foundation of China (to F Li, Grant No. 31201417) and the Shandong Provincial Natural Science Foundation (to F. Li, Grant No. ZR2018BC063). Support was also provided by the National Cancer Institute via grant R21CA184788 (to QP Dou) and by a National Institutes of Health grant P30 CA022453 (to the Karmanos Cancer Institute at Wayne State University).