Peptides and peptidomimetics in the p53/MDM2/MDM4 circuitry - a patent review

Introduction: Restoration of the p53 tumor suppressor function is an attractive anticancer strategy. Despite the development of several therapeutics targeting the two main p53 negative regulators, MDM2 and MDM4, no one has yet reached clinical application. In the past, several efforts have been employed to develop more specific and efficient compounds that can improve and/or overcome some of the features related to small molecule compounds (SMC). Peptides and peptidomimetics are emerging as attractive molecules given their increased selectivity, reduced toxicity and reduced tendency to develop tumor-resistance compared to SMC.

Area covered: This article reviews publications and patents (publicly available up to April 2016) for peptides and derivatives aimed to reactivate the oncosuppressive function of p53, with a particular focus on inhibitors of MDM2/MDM4. Emphasis is placed on the efficacy of these compounds compared to the p53-reactivating small molecules developed so far.

Expert opinion: A number of promising peptides for p53 reactivation in cancer therapy have been developed. These compounds appear to possess improved features compared to SMC, especially for their ability to simultaneously target the MDM2/MDM4 inhibitors, and their increased specificity.     

生物技术在中医药现代化研究中的应用

生物技术在中医药现代化领域的应用前景广阔。本文简述了现代生物技术在中药种植、中药鉴定的应用；基因芯片技术在中医诊断、中药新药研发等领域的应用；蛋白质组学从分子生物水平上揭示中药作用机制，具有广阔前景。     

Advancements in the anti-diabetes chemotherapeutics based on amino acids, peptides, and peptidomimetics

Diabetes Mellitus (DM) is a highly prevalent chronic disease. Recent years have witnessed development of many new oral drugs; novel insulin analogs and their delivery systems for the treatment of patients with either type-1 or type-2 DM. The impetus for developing new antidiabetic drugs comes from the unmet need of pharmacological tools that allow diabetic patients to achieve recommended glucose control targets by precise, safe and effective ways. The number of people afflicted with DM worldwide has increased considerably in recent years and is projected to increase dramatically over the next decades. In the recent times, design and synthesis of bioactive peptides and peptidomimetics has undergone a paradigm shift. Non-proteinogenic amino acids, peptides and peptidomimetics are emerging as novel drug candidates for the treatment of various diseases and/or disorders. This review mainly discusses the advancements in the usage of unnatural amino acids, peptides and peptidomimetics as potential therapeutic agents for the treatment of DM.     

Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics

A new series of 1,2,4-oxadizoles 6a-g have been synthesised in good yields using the peptide synthesis strategy. The prepared compounds were tested for anti-inflammatory and antimicrobial activities. The anti-inflammatory activities were determined in the rat paw oedema induced by carrageenin. Compounds 6a, c, f and g (i.v.) significantly inhibited the rat paw oedema induced by carrageenin depending upon the dose employed. The compounds were also evaluated for their in vitro antimicrobial activity. Some compounds were found to have significant activity against Gram positive and Gram negative microorganisms.     

Selective formation of homo- and heterobivalent peptidomimetics

Methodology is presented for assembling fluorescently labeled bivalent molecules from monovalent constituents, without side chain protection or coupling agents. To illustrate the procedure, a series of bivalent peptidomimetics directed toward the Trk receptors were prepared and screened via fluorescent activated cell sorting scan assays.     

Ring closing metathesis in the synthesis of biologically interesting peptidomimetics, sugars and alkaloids

Olefin metathesis has rapidly established itself as an essential tool in the synthetic chemist's armoury. The ease of operation and functional group tolerance that is obtained with the modern generation of catalysts makes the use of metathesis an extremely attractive option when preparing medicinally interesting molecules. This article will outline some of the ways in which chemists from both industry and academia have been utilising and developing metathesis in the search for novel biological probes and drug leads.     

Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide

In the present study, the synthesis of the 5.5.6. and 5.6.5. spiro bicyclic lactam PLG peptidomimetics, compounds 3 and 4, respectively, was undertaken. These peptidomimetics were designed to examine the following: (1) the effect that changing the size of the thiazolidine and lactam ring systems would have on the ability of these systems to mimic the type-II beta-turn and (2) the effect that these structural perturbations would have on the ability of the peptidomimetics to modulate dopamine receptors. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) dopamine D2 receptor competitive binding assay, 3 and 4, at a concentration of 100 nM, decreased the dissociation constant of the high-affinity state of the dopamine receptor for the agonist. These effects were observed when either Gpp(NH)p was absent or present and they were comparable to those produced by PLG at a concentration of 1 microM. Peptidomimetics 3 and 4 also increased the percentage of D2 receptors that existed in the high-affinity state. Even with Gpp(NH)p present, 3 and 4 were able to return the RH/RL ratios to values observed in the respective controls where Gpp(NH)p was absent. Furthermore, both peptidomimetics were able to attenuate the Gpp(NH)p-induced shift to the low-affinity state to a greater extent than PLG. Peptidomimetics 3 and 4 were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism, and each affected the rotational behavior in a bell-shaped dose-response relationship producing increases of 95 +/- 31% (0.01 mg/kg, ip) and 88 +/- 14% (0.001 mg/kg, ip), respectively. In comparison, the previously reported 5.5.5. spiro bicyclic lactam 2 increased rotational behavior by 25 +/- 11% (0.01 mg/kg, ip).     

子宫内膜异位症术后联合应用中西药治疗的临床效果

目的 探讨腹腔镜手术后联合中西药物治疗子宫内膜异位症（EM）的临床效果.方法 将94例EM患者行腹腔镜术后按随机数字法分为两组,对照组47例服用米非司酮,观察组47例则在对照组的基础上加用中药治疗,并观察两组治疗后的临床疗效.结果 观察组总有效率为95.74％明显高于对照组的82.98％（P＜0.05）,观察组的疼痛缓解率、1年内累计妊娠率均高于对照组（均P＜0.05）,而观察组的复发率、排卵恢复时间、月经恢复时间、血清CA125、不良反应发生率均低于对照组（均P＜ 0.05）.结论 腹腔镜手术联合中西药治疗EM具有疗效肯定、不良反应少、安全、可靠等优点,可有效降低复发率,并提高患者术后受孕率.     

Molecular modeling in the design of peptidomimetics and peptide surrogates

The most important natural sources of new leads are plant extracts, bacterial broths, animal venoms and peptides isolated from living organisms. However, only the three first have been used extensively in the development of new therapeutic agents. This is probably due to the low pharmacological profile exhibited by peptides, that requires a lengthy transformation to make them suitable as new leads. In contrast, bioactive compounds isolated from the other sources are regularly closer to be used as lead compounds. Nevertheless, the sources for compounds of this category are nowadays scarce. In contrast, there are new bioactive peptides discovered quite often and reported as ligands for different receptors. Under these circumstances peptides appear as an attractive source of prospective new leads. In order to reduce the time involved in the design of a potential lead from a peptide, molecular modeling tools have been developed in the last few years. The purpose of the present work is to review the different techniques available and to report various successful examples of design of new peptidomimetics published in the literature.     

Cyanobacterial Toxins and Peptides in Lake Vegoritis,Greece

Cyanotoxins (CTs) produced by cyanobacteria in surface freshwater are a major threat for public health and aquatic ecosystems. Cyanobacteria can also produce a wide variety of other understudied bioactive metabolites such as oligopeptides microginins (MGs), aeruginosins (AERs), aeruginosamides (AEGs) and anabaenopeptins (APs). This study reports on the co-occurrence of CTs and cyanopeptides (CPs) in Lake Vegoritis, Greece and presents their variant-specific profiles obtained during 3-years of monitoring (2018–2020). Fifteen CTs (cylindrospermopsin (CYN), anatoxin (ATX), nodularin (NOD), and 12 microcystins (MCs)) and ten CPs (3 APs, 4 MGs, 2 AERs and aeruginosamide (AEG A)) were targeted using an extended and validated LC-MS/MS protocol for the simultaneous determination of multi-class CTs and CPs. Results showed the presence of MCs (MC-LR, MC-RR, MC-YR, dmMC-LR, dmMC-RR, MC-HtyR, and MC-HilR) and CYN at concentrations of <1 μg/L, with MC-LR (79%) and CYN (71%) being the most frequently occurring. Anabaenopeptins B (AP B) and F (AP F) were detected in almost all samples and microginin T1 (MG T1) was the most abundant CP, reaching 47.0 μg/L. This is the first report of the co-occurrence of CTs and CPs in Lake Vegoritis, which is used for irrigation, fishing and recreational activities. The findings support the need for further investigations of the occurrence of CTs and the less studied cyanobacterial metabolites in lakes, to promote risk assessment with relevance to human exposure.     

L-PRP/L-PRF in esthetic plastic surgery, regenerative medicine of the skin and chronic wounds

The use of platelet concentrates for topical use is of particular interest for the promotion of skin wound healing. Fibrin-based surgical adjuvants are indeed widely used in plastic surgery since many years in order to improve scar healing and wound closure. However, the addition of platelets and their associated growth factors opened a new range of possibilities, particularly for the treatment of chronic skin ulcers and other applications of regenerative medicine on the covering tissues. In the 4 families of platelet concentrates available, 2 families were particularly used and tested in this clinical field: L-PRP (Leukocyte- and Platelet-rich Plasma) and L-PRF (Leukocyte- and Platelet-Rich Fibrin). These 2 families have in common the presence of significant concentrations of leukocytes, and these cells are important in the local cleaning and immune regulation of the wound healing process. The main difference between them is the fibrin architecture, and this parameter considerably influences the healing potential and the therapeutical protocol associated to each platelet concentrate technology. In this article, we describe the historical evolutions of these techniques from the fibrin glues to the current L-PRP and L-PRF, and discuss the important functions of the platelet growth factors, the leukocyte content and the fibrin architecture in order to optimize the numerous potential applications of these products in regenerative medicine of the skin. Many outstanding perspectives are appearing in this field and require further research.     

Echinacea biotechnology: advances,commercialization and future considerations

Context: Plants of the genus Echinacea (Asteraceae) are among the most popular herbal supplements on the market today. Recent studies indicate there are potential new applications and emerging markets for this natural health product (NHP).

Objective: This review aims to synthesize recent developments in Echinacea biotechnology and to identify promising applications for these advances in the industry.

Methods: A comprehensive survey of peer-reviewed publications was carried out, focusing on Echinacea biotechnology and impacts on phytochemistry. This article primarily covers research findings since 2007 and builds on earlier reviews on the biotechnology of Echinacea.

Results: Bioreactors, genetic engineering and controlled biotic or abiotic elicitation have the potential to significantly improve the yield, consistency and overall quality of Echinacea products. Using these technologies, a variety of new applications for Echinacea can be realized, such as the use of seed oil and antimicrobial and immune boosting feed additives for livestock.

Conclusions: New applications can take advantage of the well-established popularity of Echinacea as a NHP. Echinacea presents a myriad of potential health benefits, including anti-inflammatory, anxiolytic and antibiotic activities that have yet to be fully translated into new applications. The distinct chemistry and bioactivity of different Echinacea species and organs, moreover, can lead to interesting and diverse commercial opportunities.     

Recent advances in the synthesis of some bioactive peptides and peptidomimetics

This review focuses on the synthetic progress of some naturally occurring cyclic peptides and depsipeptides apart from the development of peptidomimetics incorporating unnatural amino acids that have not been covered in the earlier reviews.     

Design, synthesis and biological evaluation of glutathione peptidomimetics as components of anti-Parkinson prodrugs

Plethoras of CNS-active drugs fail to effect their pharmacologic response due to their in vivo inability to cross the blood-brain barrier (BBB). The classical prodrug approach to overcome this frailty involves lipophilic derivatives of the polar drug, but we herein report a novel approach by which endogenous transporters at BBB are exploited for brain drug delivery. The crucial role played by glutathione in pathogenesis of Parkinson's and the presence of its influx transporters at the basolateral membrane of BBB served as the basis for our anti-Parkinson prodrug design strategy. A metabolically stable analogue of glutathione is used as a carrier for delivery of dopamine and adamantamine. An account of successful syntheses of these prodrugs along with their transport characteristics and stability determination is discussed.     

以氨肽酶 N为靶点的N-取代-2，5-吡咯烷二酮类肽的设计合成及活性研究

目的 寻找具有氨肽酶N(APN,CD13)抑制活性的新型化合物并测定其抑制氨肽酶N的活性;考察目标化合物与APN活性位点的结合,研究目标化合物与酶的相互作用关系。方法 以光学纯的天冬酰胺为原料,经Boc保护、环合、酯化、脱Boc保护、酰化、氢化还原、羟肟酸化等反应合成目标化合物。借助FlexX对接软件,研究目标化合物与APN活性位点的结合情况;采用体外抑酶试验测定目标化合物抑制APN的活性。结果 合成了14个未见文献报道的 N-取代-2,5-吡咯烷二酮类肽类APN抑制剂,其结构经¹H-NMR、MS谱确证。结论 目标化合物均对APN/CD13具有一定的抑制活性,其中,化合物7h的活性较好,与计算机对接结果一致。     

Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines

Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.