抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than “S” (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area ...

/pdf/natural-products-as-sources-of-new-drugs-over-the-last-25-24stxjn5tu.pdf

Natural Products as Sources of New Drugs over the Last 25 Years

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over t...

Natural Products as Sources of New Drugs from 1981 to 2014

This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74...

/pdf/natural-products-as-sources-of-new-drugs-over-the-30-years-4p9j38phh8.pdf

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

Publisher Summary Plant-based systems continue to play an essential role in health care, and their use by different cultures is extensively documented. This chapter reviews the continuing value of natural products as sources of potential chemotherapeutic agents. While the contributions of natural secondary metabolites to modern medicine are abundantly clear, the question of their origins has long intrigued chemists and biochemists. Six major hypotheses are summarized here. Structural diversity is not the only reason why natural products are of interest to drug developers, since they often provide highly selective and specific biological activities based on mechanisms of action. The natural products approach can thus be seen as complementary to the synthetic approach, each providing access to (initially) different lead structures. The task of the natural products researcher is thus to select these compounds of pharmacological interest from the “natural combinatorial libraries” produced by extraction of organisms. There are four major elements in the design of any successful natural-products–based drug discovery program: acquisition of biomass, effective screening, bioactivity- driven fractionation, and rapid and effective structure elucidation. The selection of plant samples often raises the question of the ethnobotanical/ethnopharmacological approach versus a random approach. Structure elucidation of the bioactive constituent depends almost exclusively on the application of modern instrumental methods, particularly high-field NMR and MS. Novel methods of chemical syntheses that have the potential to produce base “natural product” molecules that can be optimized for specific medicinal chemistry purposes are also reported.

Natural Products as Pharmaceuticals and Sources for Lead Structures

A novel cytotoxic stilbene, schweinfurthin D, was isolated from Macaranga schweinfurthii (Euphorbiaceae) and its structure was determined by spectroscopic methods. Schweinfurthin D showed comparable potency to schweinfurthin B.

Schweinfurthin D, a cytotoxic stilbene from Macaranga schweinfurthii.

Impact of Natural Products on Developing New Anticancer Agents

A characteristic pattern of differential cytotoxicity of extracts of Iberis amara seeds, predominantly toward renal tumor, brain tumor, and melanoma cell lines in the NCI human disease-oriented tumor screening panel, was traced to cucurbitacins E [1] and I [2]. This same differential cytotoxicity profile was detected in extracts of Begonia plebeja and Gonystylus keithii. Computer-assisted recognition of these profiles was followed by a rapid chemical fractionation, thus permitting the efficient dereplication of those extracts containing cucurbitacins B [3] and D [4], respectively. This is the first report of cucurbitacins from the genus Gonystylus.

Cucurbitacins: differential cytotoxicity, dereplication and first isolation from Gonystylus keithii.

This review discusses the role of microbial secondary metabolites produced by organisms from all three domains of life (the Archaea, Prokarya and Eukarya) as sources of pure natural products or derivatives of natural products, and as leads for novel synthetic compounds that may have the potential to ameliorate cancer. Drugs for which a microbe has either been identified as the producer of the active component or has been associated with its production based on circumstantial evidence are discussed. In addition, the impact of the increase in available genomic information and manipulation is discussed, along with some relevant examples, leading to the realization that the potential of microbes as sources of new leads/agents or as biological probes is large.

Gordon M. Cragg

Papers

Natural Products as Pharmaceuticals and Sources for Lead Structures

Schweinfurthin D, a cytotoxic stilbene from Macaranga schweinfurthii.

Impact of Natural Products on Developing New Anticancer Agents

Cucurbitacins: differential cytotoxicity, dereplication and first isolation from Gonystylus keithii.

Microbial antitumor drugs: natural products of microbial origin as anticancer agents.