Nothing is solid about proteins. Governing rules and established laws are constantly broken. As an example, the last decade and a half have witnessed the fall of one of the major paradigms in structural biology. Contrarily to the more than a century-old belief that the unique function of a protein is determined by its unique structure, which, in its turn, is defined by the unique amino acid sequence, many biologically active proteins lack stable tertiary and/or secondary structure either entirely or at their significant parts. Such intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered domains and functional IDP regions (IDPRs) are highly abundant in nature, and many of them are associated with various human diseases. Such disordered proteins and regions are very different from ordered and well-structured proteins and domains at a variety of levels and possess well-recognizable biases in their amino acid compositions and amino acid sequences. A characteristic feature of these proteins is their exceptional structural heterogeneity, where different parts of a given polypeptide chain can be ordered (or disordered) to different degrees. As a result, a typical IDP/IDPR contains a multitude of potentially foldable, partially foldable, differently foldable or not foldable structural segments. This distribution of conformers is constantly changing in time, where a given segment of a protein molecule has different structures at different time points. The distribution is also constantly changing in response to changes in the environment. This mosaic structural organization is crucial for their functions and many IDPs are engaged in biological functions that rely on high conformational flexibility and that are not accessible to proteins with unique and fixed structures. As a result, the functional repertoire of IDPs complements that of ordered proteins, with IDPs/IDPRs being often involved in regulation, signaling and control. This Sprenger Briefs volume is dedicated to IDPs and IDPRs and an attempt is made to compress a massive amount of knowledge and into a digest that aims to be of use to those wishing a fast entry into this promising field of structural biology.

Intrinsically Disordered Proteins

Recent advances in porphyrin-based nanocomposites for effective targeted imaging and therapy

The synthesis and application of porphyrins has seen a huge shift towards research in porphyrin bio-molecular based systems in the past decade. The preferential localization of porphyrins in tumors, as well as their ability to generate reactive singlet oxygen and low dark toxicities has resulted in their use in therapeutic applications such as photodynamic therapy. However, their inherent lack of bio-distribution due to water insolubility has shifted research into porphyrin-nanomaterial conjugated systems to address this challenge. This has broadened their bio-applications, viz. bio-sensors, fluorescence tracking, in vivo magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT imaging to photo-immuno-therapy just to highlight a few. This paper reviews the unique theranostic role of porphyrins in disease diagnosis and therapy. The review highlights porphyrin conjugated systems and their applications. The review ends by bringing current challenges and future perspectives of porphyrin based conjugated systems and their respective applications into light.

https://www.mdpi.com/1420-3049/24/14/2669/pdf

Porphyrin as Diagnostic and Therapeutic Agent.

The disadvantages that come with traditional cancer treatments, such as chemotherapy and radiotherapy, generated a research shift toward nanotechnology. However, even with the important advancements regarding cancer therapy, there are still serious stepping stones that need to be addressed. The use of both nanotechnology and nanomedicine has generated significant improvements in nano-sized materials development and their use as therapeutic, diagnosis, and imaging agents. The biological barriers that come from the healthy body, as well from the tumorous sites, are important parameters that need to be taken into consideration when designing drug delivery systems. There are several aspects of extreme importance such as the tumor microenvironment and vasculature, the reticuloendothelial system, the blood-brain barrier, the blood-tumor barrier, and the renal system. In order to achieve an effective system for cancer therapy, several characteristics of the nanoparticles have been outlined. Moreover, this review has also focused on the different types of nanoparticles that have been studied over the years as potential candidates for cancer therapy.

https://www.mdpi.com/1420-3049/24/19/3547/pdf

Nanobiomaterials Used in Cancer Therapy: An Up-To-Date Overview.

Atherosclerosis is a major cause of mortality and morbidity, which is mainly driven by complications such as myocardial infarction and stroke. These complications are caused by thrombotic arterial occlusion localized at the site of high-risk atherosclerotic plaques, of which early detection and therapeutic stabilization are urgently needed. Here we show that near-infrared autofluorescence is associated with the presence of intraplaque hemorrhage and heme degradation products, particularly bilirubin by using our recently created mouse model, which uniquely reflects plaque instability as seen in humans, and human carotid endarterectomy samples. Fluorescence emission computed tomography detecting near-infrared autofluorescence allows in vivo monitoring of intraplaque hemorrhage, establishing a preclinical technology to assess and monitor plaque instability and thereby test potential plaque-stabilizing drugs. We suggest that near-infrared autofluorescence imaging is a novel technology that allows identification of atherosclerotic plaques with intraplaque hemorrhage and ultimately holds promise for detection of high-risk plaques in patients.Atherosclerosis diagnosis relies primarily on imaging and early detection of high-risk atherosclerotic plaques is important for risk stratification of patients and stabilization therapies. Here Htun et al. demonstrate that vulnerable atherosclerotic plaques generate near-infrared autofluorescence that can be detected via emission computed tomography.

/pdf/near-infrared-autofluorescence-induced-by-intraplaque-5bchatzov9.pdf

Near-infrared autofluorescence induced by intraplaque hemorrhage and heme degradation as marker for high-risk atherosclerotic plaques

With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with tetrasodium salt of meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embedment of TPPS on the gold nanosurface provides excellent stability and biocompatibility to the nanoparticles. Porphyrin interacts with the gold nanosurface through the coordination interaction between gold and pyrrolic nitrogen atoms of the porphyrin and forms a strong association complex. DOX-loaded nanocomposite (DOX@TPPS-AuNPs) demonstrated enhanced cellular uptake with significantly reduced drug efflux in MDR brain cancer cells, thereby increasing the retention time of the drug within tumor cells. It exhibited about 9 ...

Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells.

A gold nanoparticle exhibits strong absorption and emission due to its unique physical geometry and surface plasmon resonance phenomena. A further modification with organic molecules makes it more appropriate for biological applications. The current manuscript illustrated the optical behavior and stability of bilirubin (BR) coated gold (AuBR) nanoparticles, using BR itself as a reducing agent. In addition, FT-IR and steady state fluorescence measurements were performed to illustrate the binding interaction of BR with the Au(III) ion and the nanoparticles. BR showed a strong affinity towards Au(III) and the measured binding constant was ∼4.3 × 105 M−1. It caused reduction of the Au(III) ion and rendered the formation of cubic face centered AuBR nanoparticles, which were ∼20 nm in diameter. The particles were stabilized as BR was bound to the gold nanoparticle surface, which was confirmed by FT-IR measurement. An intense carboxyl CO stretching vibration at 1695 cm−1 was observed for the BR powder but was absent for the AuBR nanoparticles. However, two weak bands at ∼1563 and 1391 cm−1, presumably due to the asymmetric and symmetric stretching vibrations of the carboxylate form (COO−), were found for the AuBR nanoparticles. A stretching vibration of lactam CO appeared at 1645 cm−1 for BR and the band was shifted to 1647 cm−1 for the AuBR nanoparticles. The stretching modes of pyrrole N–H and lactam N–H were detected at 3406 cm−1 and 3267 cm−1, respectively, for BR. However, the pyrrole N–H band shifted to 3446 cm−1 and became broader for the AuBR nanoparticles. The observed blue shift in the lactam CO and N–H vibrations of the AuBR nanoparticles indicated a weakening/absence of internal hydrogen bonds between the carboxyl groups and the four N–H bonds in the BR moiety. The binding of BR to the surface provides great stability to the nanoparticles, which remained monodispersed in the large pH range (pH 4 to 12) for more than a month. However, under acidic pH conditions the particles associated to form bigger particles and the plasmon resonance band shifted as they grew; the plasmon resonance band shifted from 525 nm (at pH 7.0) to 555 nm (at pH 3.0). The particles also remained stable in the presence of a higher concentration of salt (KCl and NaCl) in the dispersing media.

Stability and binding interaction of bilirubin on a gold nano-surface: steady state fluorescence and FT-IR investigation

An analog of coomassie brilliant blue-R (CBB-R) was recently found to act as an antagonist to ATP-sensitive purinergic receptors (P2X7R) and has potential to be used in medicine. With the aim of understanding its transportation and distribution through blood, in this investigation, we measured the binding parameters of CBB-R with bovine hemoglobin (BHG). The molecule specifically bound to a single binding site of the protein with a stoichiometric ratio of 1 : 1 and the observed binding constant Ka was 3.5, 2.5, 2.0 and 1.5 × 105 M−1 at 20 °C, 27 °C, 37 °C and 45 °C, respectively. The measured respective ΔG0 values of the binding at four temperatures were −30.45, −22.44, −18.04 and −11.95 kJ mol−1. The ΔH0 (change in enthalpy) and ΔS0 (change in entropy) values were −23.6 kJ mol−1 and −70.66 J mol−1 respectively in the binding process. The negative value of ΔH0 and ΔS0 indicated that the binding of the molecule was thermodynamically favorable. The best energy structure in the molecular docking analysis revealed that CBB-R preferred to be intercalated in the cavity among the α2, β1 and β2 subunits and the binding location was 7.4 A away from Trp37 in the β2 subunit. The binding of the molecule with the protein was stabilized by hydrogen bonds involving the side chain of two amino acid residues. The residues were Lys104 and Glu101 in the β2 subunit. The binding was further stabilized via hydrogen bond formation between the amide group of the peptide backbone (residue Tyr145 of the β1 subunit) and CBB-R. A shift of the amide I (–CO stretching) band frequency of ∼8 cm−1 to low energy was ascribed to the hydrogen bond interaction involving the polypeptide carbonyl of the protein and the CBB-R molecule. In addition, two π–cation interactions between Lys99 of the α2 subunit and Lys104 of the β2 subunit and CBB-R contributed favorably in the binding processes. No substantial change in the soret and Q absorption bands of BHG could be observed in the presence of CBB-R. It indicated that the oxygen binding domain or the heme proximity was not blocked or substantially perturbed due to the binding of CBB-R. The circular dichroism and the molecular dynamics analysis further established that the binding interaction caused no significant alteration in the protein long range secondary structure.

Hydrogen bonding plays a significant role in the binding of coomassie brilliant blue-R to hemoglobin: FT-IR, fluorescence and molecular dynamics studies

Recent investigations indicated that copper oxide nanoparticles can selectively induce apoptosis and effectively suppress the proliferation of tumor cells. Thus, it showed a great potential to be used as a drug for cancer treatment. Here we report an easy synthesis of spheroidal cuprous oxide nanoparticles (CuNPs) and their organic conjugate with l-tryptophan (Trp) using surfactant, sodium dodecyl sulfate as a capping reagent. The particles looked golden yellow and showed a strong affinity to bind blood carrier proteins such as bovine serum albumin and human serum albumin. However, both optical behavior and texture of the particles altered upon conjugation with Trp. The average size of the CuNPs was estimated to be ~70 nm as appeared under transmission electron microscope or atomic force microscope. The biological conjugate with Trp was ~85 nm and looked light sky blue in aqueous suspension. The surface of the conjugated nanoparticles was smoother than the bare CuNPs. The CuNPs were found to be toxic to different cultured cancerous cells; however, conjugation with Trp attenuated the toxicity, and indicated its possible utility in developing a drug candidate for cancer in a controlled fashion. Reduced toxicity also indicated a possible use of the conjugated particle as a drug delivery system.

Copper(I) oxide nanoparticle and tryptophan as its biological conjugate: a modulation of cytotoxic effects

Silver nanoparticle shows distinctive electrochemical properties, and it has a wide range of applications in most areas of science and technology. In the current work we reported the synthesis of b...

Mritunjoy Maity

Papers

Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells.

Stability and binding interaction of bilirubin on a gold nano-surface: steady state fluorescence and FT-IR investigation

Hydrogen bonding plays a significant role in the binding of coomassie brilliant blue-R to hemoglobin: FT-IR, fluorescence and molecular dynamics studies

Copper(I) oxide nanoparticle and tryptophan as its biological conjugate: a modulation of cytotoxic effects

Sensing of Iron(III) Ion via Modulation of Redox Potential on Biliverdin Protected Silver Nanosurface