Functional proteins are the most versatile macromolecules. They can be obtained by extraction from natural sources or by genetic engineering technologies. The outstanding selectivity, specificity, binding activity, and biocompatibility endow engineered proteins with outstanding performance for disease therapy. Nevertheless, their stability is dramatically impaired in blood circulation, hindering clinical translations. Thus, many strategies have been developed to improve the stability, efficacy, bioavailability, and productivity of therapeutic proteins for clinical applications. In this review, we summarize the recent progress in the fabrication and application of therapeutic proteins. We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly. Furthermore, we highlight their diverse applications as growth factors, nanovaccines, antibody-based drugs, bioimaging molecules, and cytokine receptor antagonists. Finally, a summary and perspective for the future development of therapeutic proteins are presented. 

/pdf/engineered-protein-nanodrug-as-an-emerging-therapeutic-tool-2z23vxbv.pdf

Engineered protein nanodrug as an emerging therapeutic tool

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a popular narcotic analgesic agent that is clinically used worldwide. However, fentanyl and its several analogs have caused abuse and fatalities in humans due to overdosing and narrow therapeutic index. The present study reports the synthesis and comparative bioefficacy of fentanyl and its four analogs, viz., N-(1-propyl-4-piperidinyl)propionanilide (1), N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-(1-(3-phenoxypropyl)-4-piperidinyl)propionanilide (3) and N-(1-(2-cyanoethyl)-4-piperidinyl)propionanilide (4), where the phenethyl chain of fentanyl was replaced by different functional groups, viz., alkyl, ethereal, and nitrile moieties. The median lethal dose (LD50) of the compounds was determined by three different routes and all the analogs were found to be safer than fentanyl. Observational assessment on spontaneous activities of the central nervous system, peripheral nervous system, and autonomic nervous system revealed that all the analogs were similar to fentanyl. Further, the neurotoxic effects of all the analogs were reversed by naloxone hydrochloride (opioid antagonist), confirming that their effects were mediated through opioid receptors. Antinociceptive activity was displayed by all the compounds and their median effective dose (ED50) and analgesic potency ratio were more or less similar to fentanyl. The lowest ED50 (23.7) and the highest potency ratio (1.18) was observed in the case of 2. However, the maximum therapeutic index was afforded by 4. The study indicates the promising role of some new opioid analgesics.

Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice

Abstract Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Because of the complex pathogenesis of AD and the unique location of AD lesions, effective clinical treatment strategies for this disease remain elusive. However, the development of nanotechnology has allowed a new era of AD treatment to emerge. AD nanomedicines are products of interdisciplinary research that enable high precision and targeted delivery. Additionally, they can specifically regulate various pathogenic factors. This review focuses on nanomedicines based on the pathological mechanisms of AD that can target AD lesions. We also discuss the precise regulatory effects of nanomedicines (including the nanomaterials themselves) on pathogenic proteins, neuroinflammatory molecules, and other pathogenic factors. We summarize the clinical trials that have examined new AD drugs, highlighting the development of new nanomedicines and the progress in their clinical translation. Nanotechnology‐based AD treatment is a nascent field, and a complete cure is distant at present; therefore, we also elaborate on the shortcomings of current AD nanomedicines. Finally, we discuss the prospects to guide the future development of AD nanomedicines. 

Nanomedicines for Alzheimer's disease: Therapies based on pathological mechanisms

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, Ki = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2.

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (Ki = 0.4 ± 0.1 nM) and the highest selectivi...

The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities.

7α-Phenyl-6α,14α-endo-etheno-tetrahydrothebaine is an analogue of morphine but with much weaker affinity and efficacy to opioid receptors Three compounds with o-, m- and p-amino substitution on its 7α-phenyl group were designed and synthesized to evaluate their κ-opioid receptor agonistic activity and antinociceptive effect The introduction of amino group greatly increased the binding activity to κ-opioid receptor but only compound with p-substitution showed agonistic activity with potency similar to the marketed κ agonist butorphanol In vivo antinociceptive test showed that compound with p-amino substitution displayed highest antinociceptive activity while compounds with o-, m-amino substitution showed partial or little analgesia effects All these data indicate that p-amino substitution conferred κ agonist activity, suggesting that 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaines with a p-amino substitution may contain a novel pharmacophore component and could be considered as a leading compound for novel antinociceptive agents

http://jpkc.fudan.edu.cn/picture/article/84/72/83/ac1988cf4f0ba141b52b4c0f90a2/c7794052-ff7e-4407-8873-7278161cc550.pdf

Synthesis and evaluation of κ-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaine with substituted o-, m- and p-amino group

Cerebrovascular dysfunction characterized by the neurovascular unit (NVU) impairment contributes to the pathogenesis of Alzheimer's disease (AD). In this study, a cerebrovascular-targeting multifunctional lipoprotein-biomimetic nanostructure (RAP-RL) constituted with an antagonist peptide (RAP) of receptor for advanced glycation end-products (RAGE), monosialotetrahexosyl ganglioside, and apolipoprotein E3 is developed to recover the functional NVU and normalize the cerebral vasculature. RAP-RL accumulates along the cerebral microvasculature through the specific binding of RAP to RAGE, which is overexpressed on cerebral endothelial cells in AD. It effectively accelerates the clearance of perivascular Aβ, normalizes the morphology and functions of cerebrovasculature, and restores the structural integrity and functions of NVU. RAP-RL markedly rescues the spatial learning and memory in APP/PS1 mice. Collectively, this study demonstrates the potential of the multifunctional nanostructure RAP-RL as a disease-modifying modality for AD treatment and provides the proof of concept that remodeling the functional NVU may represent a promising therapeutic approach toward effective intervention of AD.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/advs.202001918

Multifunctional Nanostructure RAP-RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit.

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Synthesis and evaluation of κ-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaine with substituted o-, m- and p-amino group

Multifunctional Nanostructure RAP-RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit.