Current state and future perspective of cardiovascular medicines derived from natural products

https://doi.org/10.1016/j.pharmthera.2020.107698Get rights and content

Highlights

  • Characteristics and classification of natural products in cardiovascular medicine

  • Therapeutic applications and mechanisms of actions of natural product-derived cardiovascular medicine.

  • Integrative pharmacology approach of Traditional Chinese Medicine against cardiovascular diseases.

  • Geographical distribution and biosynthesis of key natural product for cardiovascular medicine.

Abstract

The contribution of natural products (NPs) to cardiovascular medicine has been extensively documented, and many have been used for centuries. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 40 years, approximately 50% of newly developed cardiovascular drugs were based on NPs, suggesting that NPs provide essential skeletal structures for the discovery of novel medicines. After a period of lower productivity since the 1990s, NPs have recently regained scientific and commercial attention, leveraging the wealth of knowledge provided by multi-omics, combinatorial biosynthesis, synthetic biology, integrative pharmacology, analytical and computational technologies. In addition, as a crucial part of complementary and alternative medicine, Traditional Chinese Medicine has increasingly drawn attention as an important source of NPs for cardiovascular drug discovery. Given their structural diversity and biological activity NPs are one of the most valuable sources of drugs and drug leads. In this review, we briefly described the characteristics and classification of NPs in CVDs. Then, we provide an up to date summary on the therapeutic potential and the underlying mechanisms of action of NPs in CVDs, and the current view and future prospect of developing safer and more effective cardiovascular drugs based on NPs.

Introduction

Cardiovascular diseases (CVDs), including stroke, heart failure (HF), arrhythmia, atherosclerosis, myocardial infarction (heart attack), cardiac hypertrophy, hypertension and angina, are a group of heart and blood vessel disorders (Joseph et al., 2017), which remain the leading cause of morbidity and mortality all over the world. An estimated 17.9 million deaths (nearly one third of all global deaths) were attributed to CVDs in 2016, which reflects an increase of 14.5% over the previous decade. Of these deaths, an estimated 7.4 million were due to coronary artery disease (CAD) and 6.7 million to stroke. In the United States of America, approximately 37.4% of men and 35.9% of women have at least one type of CVDs (Benjamin et al., 2019), with a mortality of 50.6% from CVDs in men. In addition, of the deaths from CVDs globally, over 75% are in low-income and middle-income countries due to the lack of qualified medical personnel and limited facilities (Vos et al., 2016). CVDs now account for an estimated 18% of disability-adjusted life years lost in developed countries and 10% in developing countries, which results in a serious economic burden (Du, Patel, Anderson, Dong and Ma, 2019; Joseph et al., 2017; Vos et al., 2016; Zhao, Liu, Wang, Zhang and Zhou, 2019). To make it more alarming, younger adults (18–50) tend to suffer a slightly increased risk of CVDs over the past 20 years, probably as a result of an unhealthy lifestyle (e.g. smoking, poor diet and physical inactivity). Given the increasing ageing population, the burden of CVDs is set to increase even further (Andersson and Vasan, 2018; Joseph et al., 2017). Furthermore, as human life expectancy increases with increased diagnosis and treatment options, subcategories in CVDs may change over time, especially myocardial ischemia-reperfusion (IR) injury and various forms of HF (Heusch, 2020; Ibáñez, Heusch, Ovize and Van de Werf, 2015; Marwick, Ritchie, Shaw and Kaye, 2018), increasing the desirability of developing more specific therapeutics.

From 1900-2020, a total of 302 new drugs were approved by the Food and Drug Administration (FDA) for the treatment of various CVDs. During what may be considered the golden era of CVDs drug discovery (1980-2000), the average number of FDA approved drugs was about 9.1 per year, far higher than the level before 1980. However, this number has decreased significantly over the past 2 decades, with an average of just 3.55 per year, a decline of approximately 61% compared to 20 years ago (Fig. 1A, Table S1), which stands in stark contrast to the significantly increasing new drug approvals in oncology (2 vs. 11 new molecular entities in 2019) (Khakoo et al., 2019a, Khakoo et al., 2019b). The decline is multifactorial, partly due to the rising cost of developing drugs to treat CVDs (e.g., a complicated clinical pathway for drug development, costly randomized clinical trials) and regulatory uncertainty for pharmaceutical companies (Fordyce et al., 2015). Secondly, the current regulatory environment requires a direct assessment of risks and benefits ratio, using clinically-evident cardiovascular endpoints, which commonly comprise hospitalization and mortality in many cardiovascular clinical trials (Fordyce et al., 2015). In addition, as the patents of a large number of drugs approved 20 years ago are expiring, many generic drugs have entered the market. As more and more patients have access to cheaper generic drugs, the incentive for pharmaceutical companies to develop new medicines for CVDs has declined. However, given the increasing demand for better treatment in certain CVDs (such as HF, arrhythmias), and the changing landscape of randomized clinical trials in CVDs (Jones et al., 2016), there are increasing opportunities and appetite from pharmaceutical companies for developing better cardiovascular medicines.

Natural products (NPs) refer to the extracts of animals, plants, components or metabolites in insects, marine organisms and microorganisms and the endogenous chemical or biochemical components in human and animal bodies. NP-derivatives (NDs), on the other hand, are defined as compounds derived from natural product with a semi-synthetic modification (Newman and Cragg, 2020). The NPs referred to in the following sections (mainly section 1, 3-7) include NPs (e.g. reserpine, digoxin, heparin) and NDs (e.g. verapamil, aspirin). In 1804, the isolation of morphine initiated the development of medicines based on NPs (Ag and Luch, 2009). After more than two centuries of development, a large number of natural drugs have been used clinically which were derived originally from natural sources in human history. For example, the antibiotic penicillin has saved countless lives, the timeless aspirin for secondary prevention of CVDs, and particularly the remarkable contribution of artemisinin in combating malaria, which is threatening millions of lives in developing regions. This is highlighted by the awarding of the Nobel Prize in Physiology (2015) to William C. Campbell and Satoshi Omura, and Youyou Tu for the discovery of avermectins and artemisinin, respectively (McKerrow, 2015). To date, NPs or NDs comprise 26% of new drugs currently being developed (Newman and Cragg, 2020). Over the past 40 years, approximately 61% of anticancer drugs, 50% of cardiovascular drugs and 49% of anti-infection drugs were developed significantly from NPs, indicating that NPs play an essential role for the discovery and development of new drug entities (Butler, 2005, Butler, 2008; Butler, Robertson and Cooper, 2014; Newman and Cragg, 2012). As of today, NPs have been widely used for the treatment of several cardiovascular conditions such as hypertension, HF, MI, arrhythmia, atherosclerosis, angina and coronary artery disease (CAD) (Fig. 1B). However, as more and more NPs have been identified, the discovery of new structures and activities has become increasingly difficult, and the research and development based on NPs declined and stagnated in CVDs. Recently, with the development of the emerging technologies using multi-omics, combinatorial biosynthesis, synthetic biology, analytical and computational technologies, the development of CVDs drugs based on NPs holds promise for future CVDs therapies (Luo, Cobb and Zhao, 2014; Zhu et al., 2011). In this review, we provide an up to date summary on both the clinical and pre-clinical development of NPs in CVDs, intending to provide a rationale for the development of novel NP-derived medicine in the new era of CVD epidemics.

Section snippets

Current NP-derived drugs in CVDs

Data from FDA-approved and clinical new molecular entities reveals that NPs and their derivatives occupy over one-third of all new molecular entities (Patridge, Gareiss, Kinch and Hoyer, 2016). To assess the application of NP-derived drugs in CVDs, the information of all NP-derived drugs was collected from the Drug Bank (https://www.drugbank.ca/), Therapeutic Target Database (http://db.idrblab.net/ttd/), such as drug name, disease, category, target, pathway and time to market (Table 1, Table 2

The contribution of NPs against different CVDs

To facilitate the understanding of the relationship between NPs and different CVDs, we first explored the association network among NPs, therapeutic targets, biological pathways, and relevant pharmacological effects using Cytoscape (vision 3.5.1, USA) (Otasek, Morris, Bouças, Pico and Demchak, 2019), based on the information summarised in Table 1 and Table 2 (Fig. 3A). A total of 87 NPs approved by the FDA (Table 1) and currently in registered clinical trials (Table 2) can directly interact

Myocardial ischemia reperfusion injury – An unmet clinical need

Given the changing landscape of CVD, there is growing demand for developing novel pharmacotherapy to target certain types of CVDs, such as myocardial ischemia reperfusion injury. Myocardial ischemia occurs when blood supply is partially or totally blocked, most commonly due to a buildup of atherosclerotic plaques in the major coronary arteries. A partial fixed obstruction that limits the capacity of blood flow to increase in response to an increase in metabolic demand results in angina

Polypills and Chinese patent medicines for CVD

CVDs have complex aetiology (Khetarpal et al., 2019; Ziaeian and Fonarow, 2016) and are accompanied by many other co-morbidities (such as diabetes and aging), which may result in the limited efficacy of monotherapies. At present, multitarget therapy strategies have gradually attracted researchers. Davidson and colleagues also focused their attention on multitarget therapy strategies for myocardial ischemia- reperfusion injury and provided a roadmap for clinical use (Davidson et al., 2019). The

The geographical distribution and biosynthesis of NPs in the treatment of CVD

Most NPs for CVDs are of plant-origin NPs (PNPs). Development and industrial production of PNPs will be affected by the origin and yield of NPs (Atanasov et al., 2015). According to our statistic, there are 53 plant derived natural products for the treatment of CVDs. Among them, we systematically collected the geographical distribution information of 46 plants which are the source of 53 PNPs in the treatment of CVDs from the Global Biodiversity Information Fund database (http://www.gbif.org/) (

Concluding remarks and perspectives

In summary, despite the significant progress made in the diagnosis and treatment over the past decades, CVDs remain a serious global health problem, suggesting that it remains an unmet clinical need for the development of innovative strategies for CVDs. Importantly, the landscape of CVDs has been evolving, due to the aging population and increased incidence of other comorbidities, such as obesity and diabetes (Joseph et al., 2017; Redfern et al., 2020; Townsend et al., 2016). Despite the

Conflict of Interest Statement

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China [Grant No. 81830111 and 81774201], National Key Research and Development Program of China [2017YFC1702104, 2017YFC1702303], the Youth Innovation Team of Shaanxi Universities and Shaanxi Provincial Science and Technology Department Project [No. 2016SF-378], the Fundamental Research Funds for the Central public welfare research institutes [ZXKT17058]. CXQ is Australia National Heart Foundation Future Fellow.

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