RS-66271: Molecular design and in vivo bone anabolic activity

Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

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Molecular Design of Polymer-based Carriers for Plasmid DNA Delivery In Vitro and In Vivo

Chemistry Letters ◽

10.1246/cl.190696 ◽

2020 ◽

Vol 49 (1) ◽

pp. 1-9

Author(s):

Shoichiro Asayama

Keyword(s):

Plasmid Dna ◽

Molecular Design ◽

Dna Delivery

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Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2012266117 ◽

2020 ◽

Vol 117 (49) ◽

pp. 31070-31077 ◽

Cited By ~ 1

Author(s):

Nasir K. Bashiruddin ◽

Mikihito Hayashi ◽

Masanobu Nagano ◽

Yan Wu ◽

Yukiko Matsunaga ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Cyclic Peptides ◽

Treatment Options ◽

Affinity Maturation ◽

Great Promise ◽

Anabolic Activity ◽

Anabolic Treatment ◽

Increase Bone Formation

Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D–treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis.

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Red Room-Temperature Phosphorescent Diimides: Molecular Design and Application

10.26434/chemrxiv.9784865 ◽

2019 ◽

Author(s):

Jiajun Du ◽

Fan Liao ◽

Ziye Wu ◽

Wenhuan Huang ◽

Fei Li ◽

...

Keyword(s):

Charge Transfer ◽

Room Temperature ◽

Molecular Design ◽

Intramolecular Charge Transfer ◽

Imaging Studies ◽

Oxygen Sensitive ◽

Photo Induced Electron Transfer ◽

Naphthalene Diimides ◽

Transfer State

N-Substituted naphthalene diimides (NDIs) were explored as purely organic room temperature phosphorescence (RTP) materials based on the strategy of intramolecular charge-transfer (ICT) mediation. A series of NDIs were designed and investigated for their luminescence properties. All emissive NDIs exhibited similar red RTP (emission range from ~600 to ~800 nm) in solid state media; the quantum yield (QY) of the obtained RTP relies heavily on the N-substitution. From poor to moderate to strong donor moieties, the QY increases but suddenly disappears. First-principle calculations reveal that a “sweet spot” for strong NDI RTP exists: while a suitable charge-transfer state can enhance RTP, a strong donor may cause total triplet quenching through the photo-induced electron transfer (PET) mechanism. Furthermore, combining NDI aggregation effects, we realized the reddest RTP ever reported for purely organic materials (Max emission = 675 nm, QY = 21.7%). Given the red emission, respectable QY and oxygen sensitive properties for some of the NDIs, they were tested as imaging agents for in vivo imaging studies.

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EXPERIMENTAL EVALUATION OF SOURCE PLANTS OF DUGDHIKA (EUPHORBIA HIRTA LINN. AND EUPHORBIA THYMIFOLIA LINN.) FOR ANABOLIC ACTIVITY: AN IN VIVO STUDY

International Journal of Research in Ayurveda and Pharmacy ◽

10.7897/2277-4343.1106201 ◽

2020 ◽

Vol 11 (6) ◽

pp. 140-148

Author(s):

Yashaswini B K ◽

Seema Pradeep ◽

Suresh Janadri ◽

Rachana K L ◽

Varuni B G

Keyword(s):

Body Mass ◽

Fat Body ◽

Abdominal Circumference ◽

Physical Parameters ◽

Alcoholic Extract ◽

Euphorbia Hirta ◽

Anabolic Activity ◽

Anabolic Action ◽

Source Plant

Rajakshavaka a drug, mentioned in Brimhaniya Maha Kashaya Gana of Charaka is mentioned as Dugdhika by Chakrapani in his commentary and in Bhava Prakasha KC Chunekar commentary, 4 sources are mentioned for the same. Among 4 sources only 2 sources are locally available i.e., Euphorbia hirta Linn and Euphorbia thymifolia Linn. These 2 sources were selected to evaluate Brimhana (Anabolic) action experimentally to understand the better source plant for Dugdhika among locally available sources. The objective of the Study is to experimentally evaluate the drug Dugdhika (Europhobia hirta Linn. Europhobia thymifolia Linn) with respect to its anabolic activity. Anabolic activity was estimated in Wistar rats by administering Hydro-alcoholic extract of Euphorbia hirta Linn (HAEEH) and Euphorbia thymifolia Linn (HAEET) with Normal and High Protein Diet (HPD: Protein – 39.4%, Fat – 10.0%, Fibre – 4.3%, Carbohydrates - 7.0 %). Anabolism was evidenced by physical parameters (Weight, Nose to Anus length, Chest Circumference, Abdominal circumference, BMI), Lean body mass (LBM), Fat body mass (FBM) and Biochemical and Haematological parameters. Both the sources of Dugdhika (Euphorbia hirta Linn and Euphorbia thymifolia Linn) showed significant anabolic action. But, among the two sources Euphorbia thymifolia Linn was more significant compared to Euphorbia hirta Linn with HPD. The obtained results revealed that, among the two locally available sources of Dugdhika (Euphorbia hirta Linn and Euphorbia thymifolia Linn) Euphorbia thymifolia Linn is a better source plant for Brimhana action.

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Design of AIEgens for Near-Infrared IIb Imaging Through Structural Modulation at Molecular and Morphological Levels

10.26434/chemrxiv.10728086 ◽

2019 ◽

Author(s):

yuanyuan li ◽

Zhaochong Cai ◽

shunjie liu ◽

Haoke Zhang ◽

sherman Wong ◽

...

Keyword(s):

Blood Vessels ◽

Fluorescence Imaging ◽

Near Infrared ◽

Molecular Design ◽

Organic Dyes ◽

Tissue Imaging ◽

Deep Penetration ◽

Structural Modulation ◽

Organic Fluorophore

<p>Fluorescence imaging in near-infrared IIb (NIR-IIb, 1500-1700 nm) spectrum holds a considerable promise for tissue imaging with deep penetration and high spatial resolution owing to the minimized autofluorescence and suppressed photon scattering. While few inorganic NIR-IIb fluorescent probes have been reported, their organic counterparts are still underdeveloped, possibly due to the lack of efficient materials with long emission wavelength. Herein, we propose a new molecular design philosophy to develop organic NIR-IIb fluorophores with high quantum yield (QY) by manipulation of the effects of twisted intramolecular charge transfer and aggregation-induced emission at the molecular and morphological levels. A pure organic fluorescent dye emitting up to 1600 nm with a QY of 14.2% in the NIR-II region (1000-1600 nm) is developed. For the first time, NIR-IIb fluorescence imaging of blood vessels and deeply-located intestinal tract of live mice based on organic dyes is achieved. The results show that organic fluorophore performs superb imaging ability in both superficial blood vessels and internal organs with high resolution and enhanced signal-to-background ratio in NIR-IIb region. We hope this groundbreakingly study will inspire further research on the evolution of pure organic NIR-IIb probes for in vivo imaging.</p>

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Recent Advances in the Design and Development of anticancer molecules based on PROTAC technology

Current Medicinal Chemistry ◽

10.2174/0929867327666200312112412 ◽

2020 ◽

Vol 27 ◽

Author(s):

Zere Mukhamejanova ◽

Yichen Tong ◽

Qi Xiang ◽

Fang Xu ◽

Jiyan Pang

Keyword(s):

High Selectivity ◽

Molecular Design ◽

Anticancer Therapy ◽

High Potency ◽

Wide Range ◽

Therapy Field ◽

Vitro Data ◽

In Vitro Data

(Proteolysis targeting chimera) degraders based on protein knockdown technology now are suggested as a novel option for the treatment of various diseases. Over the last couple of years, application of PROTAC technology has spread in a wide range of disorders, and plenty of PROTAC molecules with high potency have been reported. Mostly developing for anticancer therapy, these molecules show high selectivity to target proteins, ability to significantly induce degradation of oncoproteins, good in vivo and in vitro results. In this review, we summarized the recent development of PROTAC technology in the anticancer therapy field, including molecular design, types of targeted proteins, in vivo and in vitro data results. Additionally, we also discuss on the prospects and challenges for application of candidates based on PROTAC strategy in clinical trials.

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Radiolabeled GRPR Antagonists for Imaging of Disseminated Prostate Cancer - Influence of Labeling Chemistry on Targeting Properties

Current Medicinal Chemistry ◽

10.2174/0929867327666200312114902 ◽

2020 ◽

Vol 27 (41) ◽

pp. 7090-7111 ◽

Cited By ~ 2

Author(s):

Bogdan Mitran ◽

Vladimir Tolmachev ◽

Anna Orlova

Keyword(s):

Prostate Cancer ◽

Molecular Imaging ◽

Rational Design ◽

Molecular Design ◽

Short Review ◽

Special Focus ◽

Strong Impact ◽

Blood Proteins ◽

Normal Tissues

Background: Radionuclide molecular imaging of Gastrin-Releasing Peptide Receptor (GRPR) expression promises unparalleled opportunities for visualizing subtle prostate tumors, which due to small size, adjacent benign tissue, or a challenging location would otherwise remain undetected by conventional imaging. Achieving high imaging contrast is essential for this purpose and the molecular design of any probe for molecular imaging of prostate cancer should be aimed at obtaining as high tumor-to-organ ratios as possible. Objective: This short review summarizes the key imaging modalities currently used in prostate cancer, with a special focus on radionuclide molecular imaging. Emphasis is laid mainly on the issue of radiometals labeling chemistry and its influence on the targeting properties and biodistribution of radiolabeled GRPR antagonists for imaging of disseminated prostate cancer. Methods: A comprehensive literature search of the PubMed/MEDLINE, and Scopus library databases was conducted to find relevant articles. Results: The combination of radionuclide, chelator and required labeling chemistry was shown to have a significant influence on the stability, binding affinity and internalization rate, off-target interaction with normal tissues and blood proteins, interaction with enzymes, activity uptake and retention in excretory organs and activity uptake in tumors of radiolabeled bombesin antagonistic analogues. Conclusion: Labeling chemistry has a very strong impact on the biodistribution profile of GRPRtargeting peptide based imaging probes and needs to be considered when designing a targeting probe for high contrast molecular imaging. Taking into account the complexity of in vivo interactions, it is not currently possible to accurately predict the optimal labeling approach. Therefore, a detailed in vivo characterization and optimization is essential for the rational design of imaging agents.

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