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The Drug Delivery System—liposome (part one)

As a good drug carrier, liposomes have the characteristics of wide range of drug loading, high efficiency and low toxicity, can increase the stability and solubility of the drug contained, and give drug delivery characteristics such as drug targeting and slow release, and can effectively improving the bioavailability of drugs. Liposome has been a hotspot in the field of research.
In this article, the construction of liposomes from the results of liposome results, particle size design and screening of preparation methods are discussed.

Liposomes are single-layer or multi-layer vesicles with an aqueous phase inside, which are composed of ordered lipid bilayers. They have a bilayer structure similar to biofilms, so they are called artificial biofilms. The main building materials are phospholipids and cholesterol, in which the phospholipid molecule contains a polar phosphate group and two non-polar long hydrocarbon chains, so it is amphiphilic. Under specific conditions, the polar head and polar head of the phospholipid molecules polymerize, and the non-polar tail and non-polar tail polymerize to form a stable bilayer structure. All liposomes can contain water-soluble and lipids, respectively. Soluble drugs have a wide range of drug loading in the phospholipid bilayer and internal water phase. In addition, because liposomes are easily phagocytosed by monocyte phagocytic systems represented by macrophages when they enter the body, liposomes have good passive targeting of organs with developed monocyte phagocytic systems such as the liver and spleen, so it is an ideal drug carrier for treating diseases such as liver parasitic disease, leishmaniasis, leukemia, rheumatoid arthritis. Compared with ordinary preparations, the drug contained in liposomes has the characteristics of slow drug release, which can effectively improve the bioavailability of drugs. In addition, liposomes have strong penetration and retention effects (EPR) in the tumor microenvironment, so they are often used as carriers of antitumor drugs. Based on the above characteristics, liposomes have become hotspots in research and application in many fields. In recent years, the emergence of some new liposomes such as magnetic liposomes, heat-sensitive liposomes, pH-sensitive liposomes, etc. have also attracted people's attention. So far, more than 10 kinds of liposome drugs have been marketed in many countries, such as the antitumor drug doxorubicin liposome (Caelyx?), Vincristine sulfate liposome (Marqibo?), Etc.
1.Liposomal design
Liposomes can be structurally divided into monolayer liposomes, multilayer liposomes, and polycystic liposomes, where monolayer liposomes include large monolayers and small monolayer liposomes. Affected by the physicochemical properties of drug oil-water partition coefficient, ionoelectricity, etc., different types of drugs and liposome carriers have different minimum rules, so they show different drug loading trends. According to this law of action, corresponding liposome structure, or proper modification of the membrane material and drug structure can effectively improve the encapsulation efficiency of liposomes, increase drug loading and stability.
1.1.1 Drug oil-water partition coefficient and drug loading position
The oil-water partition coefficient P is an important physical and chemical property of a drug, and refers to the ratio of the concentration of the drug in the oil phase to the water phase in an equilibrium state. It can be used to predict the solubility and pharmacokinetic characteristics of drugs in vehicles, and provide theoretical basis for dosage form design. Generally, the lgp of fat-soluble drugs is greater than 4.5, and the lgp of water-soluble drugs is less than 0.3. The lgp of amphiphilic substances is between two values. Liposomes are designed to be hydrophilic and lipophilic, which can contain both water-soluble and fat-soluble substances. However, due to the characteristics of the drug and the structure of the liposome, the suitable positions of drugs with different properties are different. Fat-soluble drugs are usually embedded in the phospholipid bilayer membrane, which can achieve a higher encapsulation rate, which can accordingly increase the solubility of hydrophobic drugs and extend the systemic circulation time. Huan Yu et al. constructed ginsenoside Rg3 liposomes, which are hydrophobic anticancer active ingredients of ginseng, using lecithin as the membrane material, with an encapsulation rate of 82.47%. The pharmacokinetic parameters Cmax and AUC were increased to the normal solution group 1.19 and 1.52 times. Other studies have shown that the use of a systematic optimization scheme (DOE) can increase the encapsulation efficiency of the antifungal hydrophobic drug itraconazole to about 90% and greatly increase its solubility. Although water-soluble drugs are easily soluble in the external aqueous phase during the liposome construction process, the volume of the external aqueous phase water and the medium is generally larger than the internal aqueous phase volume. Therefore, a considerable part of the water-soluble drugs are retained in the external aqueous phase. When prepared by the traditional method, the water-soluble drug stays in the external water phase, so when the traditional method is used for preparation, the encapsulation rate of the water-soluble drug is generally not high. Haran et al. found that the encapsulation efficiency of daunorubicin, epirubicin and doxorubicin increased with the increase of oil-water partition coefficient.
To be continued in Part Two…

publié le samedi 18 janvier à 06:21, aucun commentaire.

Facts about mesenchymal stem cells

Bone marrow primitive mesenchymal stem cells are bone marrow stromal stem cells. They are a subpopulation of cells found in mammalian bone marrow stromal cells that have multiple differentiation potentials to form bone, cartilage, fat, nerves and myoblasts. They not only have mechanical support for hematopoietic stem cells (HSC) in the bone marrow, but also secrete a variety of growth factors (such as IL-6, IL-11, LIF, M-CSF, and SCF) to support haemopoiesis. Mesenchymal stem cells (MSCs) are a type of early undifferentiated cells that have the characteristics of self-renewal, self-replication, unlimited proliferation, and multidirectional differentiation. They can secrete cytokines to reduce inflammation, reduce tissue cell apoptosis, and promote proliferate and perform immune regulation of endogenous stem progenitor cells, so as to achieve the effect of repairing tissues and organs. After continuous subculture and cryopreservation, it still has the potential for multi-directional differentiation, which is called "universal cells" in the medical community.

Functions of mesenchymal stem cells

Multi-directional differentiation: they have strong proliferation ability and multi-directional differentiation potential;
Immunomodulation: they are low immunogenicity, with immunoregulatory function. They won’t cause immune rejection, and can inhibit rejection;
Rich in quantity: they are rich in various tissues and easy to collect.
Strong fertility: up to 1 billion cells can be cultured in vitro for multiple uses.
Safe and reliable: their genes are stable, not easy to mutate, and still have the characteristics of stem cells after multiple passages.
Awide range of application: they have a wide range of applications and can be used to treat almost all tissue damage, aging and degenerative diseases.
Applications of mesenchymal stem cells in humans

The cells are differentiated into functional cells, replacing functional cells that are in decline or injury;
Start the sequential expression of regeneration-related genes, so that endogenous decline of tissues and organs and damage repair are initiated;
Exogenous cells enter the body, secrete a variety of growth nutrition factors, and improve the internal microenvironment of tissues and organs;
Immunomodulation can reduce the inflammatory response of local tissues and organs;
Activate and improve the quality of immune cells and eliminate and prevent hidden diseases
Differentiate skeletal muscle cells, make fat distribution even, muscles firm, muscles and bones soft;
Promote collagen production, a variety of growth factors secreted by cells, effectively regulate the endocrine system and hormone system.
Diseases available for mesenchymal stem cells

① Hematological diseases: mainly for leukemia;

②Nervous system diseases: such as Parkinson's syndrome, Alzheimer's disease, traumatic brain injury, spinal cord injury, motor neuron disease, etc .;

③ Parenchymal organ damage or disease: such as cirrhosis and its complications, lung and other tissue fibrosis;

④ Immune system diseases: mainly use the immune regulation of stem cells, such as systemic lupus erythematosus, rheumatoid arthritis, etc .;

⑤ Cardiovascular diseases: such as myocardial infarction, vascular disease, ischemic heart disease, etc .;

⑥ Metabolic diseases: such as diabetes and its complications;

⑦ Patellar joint diseases: such as osteoarthritis, femoral head necrosis, etc .;

⑧Reproductive system diseases: such as premature ovarian failure, endocrine disorders, etc.

⑨ Other fields, such as corneal stem cells for eye diseases, stem cell anti-aging, etc.

Creative Biolabs can provide phenotypic, genetic, and functional assessments of your MSC population of interest using various techniques and tools. We adapt to your requirements by providing either individual service modules or a fully comprehensive service package.
publié le jeudi 16 janvier à 13:18, aucun commentaire.

The Introduction to Actinomycin

What is the actinomycin?

Actinomycin is a compound with an orange-red chromophore, which connects penta peptidolactone through two amide bonds. These compounds have antitumor, antibacterial, antiviral and antituberculous activities. Actinomycin D has been used clinically as an anti-tumor drug, but because of its strong toxicity, it is limited to the treatment of malignant tumors.

Biosynthesis of actinomycin

Actinomycin biosynthesis is divided into three stages. Firstly, 4-methyl-3-hydroxyanthranilic acid was synthesized through the canine urinary ammonia pathway, and then 3-hydroxy-4-methylo-aminobenzoic acid cyclopentapeptide lactone was generated under the assembly of non ribosome enzyme system. Finally, two 3-hydroxy-4-methylo-aminobenzoic acid cyclopentapeptide lactones were condensed to form phenoxazinone chromophore.

In this stage, 3-hydroxy-4-methyl-o-benzoic acid is produced by tryptophan via the canine urinary ammonia pathway. Firstly, tryptophan-2, 3-dioxygenase, kynurenine formamide and kynurenine 3-monooxygenase were used to produce 3-hydroxykynurenine.

Synthesis of non-ribosomal peptides
Although the cyclic peptides of actinomycin contain the unusual amino acids sarcosine, N-methyl valine and D-valine, they are all free protein amino acids, which are formed under the modification of non-ribosomal peptide synthetase system.

Formation of phenoxazinone chromophore
The last step of actinomycin biosynthesis is the oxidation of two 3-hydroxy-4-methylo-aminobenzoic acid cyclopentapeptide lactones, condensation to form phenoxazinone chromophore. In this part of actinomycin synthesis, more research has been done on phenoxazinone syntheses (PHS). It is an oxidase with many copper atoms and has two different oligomer forms: a dimer with low activity and a hexamer with high activity. In the early stage of culture, when no actinomycin is produced, the strain mainly contains dimer form, while when actinomycin is produced, it mostly contains hexamer form.

Biological activity of actinomycin

It is generally believed that actinomycin has antibacterial, antitumor and antiviral effects, and has been used in the clinical treatment of some malignant tumors. Its main mechanism is to interfere with the synthesis of nucleic acids and inhibit the replication of DNA viruses. In addition, it has been found that actinomycin can also play its anti-virus role by inducing cell differentiation, inducing cell apoptosis, inhibiting some protease activities and affecting cell cycle tumor activity.

Antibacterial and antiviral effects of actinomycin
Actinomycin plays an anti-bacterial and antiviral role by binding with DNA to inhibit RNA synthesis. It is found that actinomycin D can quickly penetrate through most cell membranes through osmosis and selectively accumulate in the nucleus, which indicates that actinomycin D generally targets on DNA. Actinomycin D selectively binds to guanine in DNA, inhibits RNA polymerase using DNA as a template, thus inhibiting RNA synthesis and cancer cell growth. Actinomycin D is a kind of RNA synthesis inhibitor. By inserting the phenoxazinone fused ring between the G C base pairs, its chain is projected into the small groove of the DNA helix double chain, and then combined with the hydrogen bond to the guanine residue.

Actinomycin x2 has a significant inhibitory effect on Coxsackie B3 virus (CVB3). CVB3 is the most common pathogen of viral myocarditis. When the virus enters the human body, it first propagates in the epithelial cells and lymphoid tissues of the digestive tract, including the pharynx, and then into the blood circulation, causing viremia. The virus then passes through the vascular endothelial barrier and invades the sensitive secondary target organs or tissues, causing a variety of pathological changes, of which inflammation is a special clinical manifestation of the main pathological change. At low concentrations, actinomycin x2 has a significant inhibitory effect on Escherichia coli and Bacillus subtilis. The minimum inhibitory concentration on Bacillus subtilis is 0.08mg/l, and the minimum inhibitory concentration on Escherichia coli is 40mg / L. Moreover, actinomycin x2 has strong germicidal ability on Bacillus cereus, and the germicidal ability on germinating bacillus is stronger than that on dormant bacillus, The ability of bacteria can kill the budding spores at a lower concentration, but it can kill the dormant spores at a higher concentration.

Antitumor effect and mechanism of actinomycin
It was found that actinomycin exerts its antitumor activity by influencing nucleic acid synthesis, inducing cell differentiation and apoptosis, inhibiting some protease activities and affecting the cell cycle. Actinomycin D has a strong effect on human leukemia cell line. But the cytotoxic effect of actinomycin X2 is much greater than that of actinomycin D.

Effect on nucleic acid synthesis

Actinomycin can inhibit the mitosis of mammalian cells in vitro and cause the gradual disappearance of chromosome RNA. The morphological observation of HeLa cells and some tumor cells of mice showed that actinomycin D could cause nucleolar fragmentation and chromosome breakage. In addition, it is speculated that Act23-21 may inhibit the synthesis of rRNA in nucleolus. Tritium labeling experiments on sensitive tumor cells show that Act23-21 has a strong inhibition on the synthesis of RNA in tumor cells, but a weak and slow inhibition on DNA and protein synthesis. Therefore, Act23-21 may be secondary to the inhibition of RNA synthesis, thus affecting the growth and proliferation of tumor cells.

Inducing differentiation of tumor cells

Actinomycin D can induce the differentiation of red blood cells and bone marrow red blood cell stem cells in mice at low doses. At a very low concentration, it can strongly induce the differentiation of mouse erythroleukemia cells.

Effect on tumor cell cycle

The changes in tumor cell cycle caused by high concentration of actinomycin x2 are the block of S and G2/M stages, which indicates that actinomycin x2 may be killed in the synthesis stage of DNA, which may completely kill tumor cells and prevent metastasis and spread of cancer.

Inducing apoptosis of tumor cells

Actinomycin D can bind to DNA molecules and block the activity of RNA polymerase, inhibit RNA synthesis, initiate pre apoptosis cascade reaction, produce apoptosis, and have a strong ability to induce apoptosis. Actinomycin D can also activate intracellular signals, provide co stimulation signals with Fas in the process of inducing apoptosis, and make the cell lines that are not sensitive to Fas antibody mediated apoptosis become sensitive, thus promoting apoptosis.

Development of actinomycin analogues

Actinomycin is a kind of antibiotics with good antitumor effect, but it has great toxicity, which limits its application scope. People reduce its toxicity through structural modification. The antitumor effect of actinomycin may be closely related to its common chromophore structure, while the cyclopeptide may act as a carrier. Based on this assumption, a series of related compounds have been synthesized and prepared to carry out the screening test of anti-animal tumors, so as to obtain compounds with high efficacy, low toxicity and economic benefits for tumor treatment.
publié le mercredi 15 janvier à 13:22, aucun commentaire.

The first medicine to prevent migraine during past decades

In 2018, an article published in Nature Reviews Drug Discovery showed that the FDA has approved 475 G protein-coupled receptor (GPCR) -related targeted drugs, accounting for 34% of all FDA-approved drugs.

However, these drugs are all small molecules or peptides. The FDA has not yet approved any monoclonal antibody-based GPCR targeted drugs for marketing, and only Japan has previously approved the listing of a GPCR antibody drug targeting CCR4.

GPCR is the largest membrane protein family in the human body, with more than 800 members. At this stage, there are about 370 GPCR proteins that can be drug targets. The target of star drug liraglutide (polypeptide drugs), GLP- 1R, also belongs to the GPCR family. However, members of the GPCR family have a very conservative spatial structure, low natural expression, and difficult to purify. It is difficult to prepare biologically active GPCR antigens, which makes the development of GPCR antibody drugs difficult.

On May 17, the FDA approved Amgenig (erenumab-aooe) for marketing. Patients will be given subcutaneous injections once a month to prevent migraine in adults. It should be noted that Aimovig is the first Calcitonin gene related peptide (CGRP) antibody drug approved by the FDA, sinch CGRP belongs to the GPCR family, which means that Aimovig is the first GPCR antibody drug approved by the FDA .

The efficacy of Aimovig has been confirmed in 3 clinical studies. In the first study, 955 patients with a history of migraine intermittent attacks were compared. The efficacy difference between Aimovig and placebo was compared. After 6 months of treatment, the number of headache episodes per month in the administration group was 1 to 2 days less than that in the placebo group. ; The second study enrolled 577 patients with intermittent migraine attacks. After 3 months of treatment, the average number of headache episodes per month in the administration group was one day less than that of the placebo group. The third study enrolled 667 patients with chronic migraine. For patients with a history of seizures, after 3 months of treatment, the average number of headache episodes per month in the administration group was 2.5 days less than in the placebo group. The most common adverse reactions in the study included injection site reactions and constipation.

Amgen / Novotel jointly share Aimovig's US market rights, pricing its treatment costs at $ 6,900 / year. Express Scripts has previously warned Amgen / Novartis that the cost of treatment of $ 8,000-10,000 / year is unacceptable. As a result, Aimovig's pricing not only made Express Scripts very satisfied, but also far lower than the 8500 estimated by the American Institute of Clinical Economics and Evaluation USD / year.

Apparently, Amgen has learned lessons from the pricing of PCSK9 monoclonal antibody Repatha (Evolocumab)d. Migraine is a tens of billions of dollars in the blue ocean market. Amgen Aimovig ’s first-mover advantage over Eli Lilly and Teva candidate products may not last long, and there is no significant advantage in terms of efficacy. Therefore, choose a price that is easily accepted by all parties. It is Amgen's highest priority to occupy the market as soon as possible.

Symptoms of migraine

Migraine usually shows recurrent mild to severe headaches, which are often intolerable during attacks and severely affect sleep quality. It is also accompanied by nausea, anxiety, depression, etc., which can affect adolescents' social skills and academic performance, and directly cause decline in working capacity. Migraine affects about 10% of the world's population, and the incidence of women is three times that of men. There are approximately 36 million migraine patients in the United States, 8 million patients in Japan, and approximately 13 million patients in China. Because the pathological mechanism has not been fully elucidated, there are still no drugs that can completely cure migraine.

The triptan drugs that appeared in the 1990s only relieved the degree of headaches during migraine attacks and did not prevent migraine attacks. Since then, there have been no breakthrough drugs on the market. In April 2014, the FDA approved the old drug topiramate (approved for the prevention of epilepsy in 1996 and adult migraine in 2004) for the prevention of migraine attacks in adolescents. In 2015, the American Headache Society / American Academy of Neurology Published recommendations for migraine treatment guidelines continue to be triptotans (amotetriptan, eritoran, rosettan, sumatriptan, and zomtriptan), ergotamine derivatives (dihydroergotamine nasal Sprays and inhalants), non-steroidal anti-inflammatory drugs (diclofenac and ibuprofen) and other old medicines, it can be seen that migraine is a disease with far unmet medical needs.

The release level of CGRP increases significantly during migraine attacks, and it is positively correlated with the degree of headache. It is currently considered to be the most potential target for migraine treatment and prevention. Aimovig is the first CGRP monoclonal antibody approved by the FDA, and the first new FDA-approved migraine prevention drug in nearly 20 years. Some optimistic analysts had predicted that the first CGRP inhibitor migraine drug to be launched on the market would have a maximum annual sales of US $ 12.5 billion, and the latter would only total a few billion US dollars.
publié le mardi 14 janvier à 13:02, aucun commentaire.

Methods of de novo drug design by computer-aiding (part two)

Molecular fragmentation
The molecular fragment approach is nicknamed the chemical number holding algorithm or the fragment joining algorithm, and was proposed by Qu et al. in 1991. The basic structure applied by this method is fragments. Each fragment is composed of a single functional group (such as a hydroxyl group, a phenyl group, or a benzene ring, etc.). It is divided into fragment connection methods and fragment growth methods according to the different connection and growth methods of each fragment.

(1) Fragment connection method (or linked-fragment approach): first, there must be a fragment library storing various fragments and a linker library of various linkers. Linkers are -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH = CH-, -C00-, -CONH-, -O-. During the operation, a network is first created in the receiving point region of the receptor. The surface properties of the receiving point are analyzed with probe atoms, such as hydrophobicity, fluorine bonds, static electricity, and van der Waals' gravitation. Subregions that can accommodate a fragment, such as hydrogen-bonded donors, hydrogen-bonded acceptors, fat hydrophobic, aromatic hydrophobic, and electrostatic interaction zones. Then search the debris library to find the matching shape and quality of the debris. Then search the linker library, find the appropriate linker, connect the fragments of each sub-region, and you can get a complete molecule. A series of molecules produced is optimized by molecular mechanical calculations to select the best ones The structure is for further study.

The software of the fragment connection method includes CAVFAT, SPLICE. HOOK, NEWLEAD and PRO-LIGAND.

(2) Fragment growth (fragment build): similar to the atom build, but at the receptor receiving point according to the nature and shape of the requirements, using fragments instead of atoms to grow one by one to build molecules. The starting point for fragment generation can be the seed atom specified on the recipient point, or the core fragment. Core fragments are fragments that can be attached to the acceptor point and can be obtained from the fragment library, or a fragment of the ligand molecule is selected. Then, fragments are grown according to the amount of energy, and a complete molecule is finally obtained. From a series of structures obtained by optimization of molecular mechanics, a reasonable structure was selected for further research.

Since the fragmentation method uses chemically reasonable fragments as the basic unit for design, the obtained new molecules are easy to accept in structure, so this method has become the mainstream of new drug design.

There are many design software for the fragment growth method, such as LUDI, LEAPFROG, SPROUT, CLIX, GROW, SPLICE, GROMOL and GEMINI.

LUDI (Biosym), which distinguishes four types of interaction sites between receptors and ligands:

(I) Hydrogen-bonded donors and hydrogen-bond acceptors can find sites where hydrogen bonds can be formed; (2) Aliphatic lipophilic sites and aromatic lipophilic sites, which can find suitable positions for hydrophobic interactions.

After determining the site of action, fill in the site with structural debris. Use a certain distance as a search criterion to search for suitable receiving points in groups of 2, 3, and 4 groups. A suitable fragment was retrieved from the library and filled in. If the fragment overlaps with the recipient without Fan Lihua and is electrically rejected, only the distance is appropriate, the fragment can be accepted. "The fragments are connected to form a fragment that is not connected with a real bond, and it is enough to simply lead the compound in the form of one or more points connected, and then artificially interfere, design and optimize the structure of the compound to obtain the lead compound.

LEAPFROG (Tripos) is similar to LUDI, but it can quickly calculate the energy of a large number of candidate compounds and eliminate compounds with inappropriate energy. It has three main functions for post-processing: (1) Structural optimization (Optimize), The lead compound is optimized for structure; (2) Dream, a new lead compound is fictional; (3) Guide, which guides the user's proposed structure optimization scheme.

4.Homologous protein modeling

Direct drug design must know the three-dimensional structure of the receptor. However, so far, the X aromatic number receptor protein only knows the sequence of amino acids, and its three-dimensional structure is unknown, and there is no method to predict the three-dimensional structure of a protein from the primary structure of the protein.

Homologous protein maintains structural guidance during evolution, that is, homology.

For example, aspartic protease and peniclllopepsin, rhizopuspcpsin, fungal enzymes such as pepsin and cndothiapcpsin, and mammalian enzymes such as porcine pepsin, have a certain degree Homology. From the comparison of their structural sequences, it is not difficult to see that there are structurally conserved regions (SCRs) and variable regions (VRs) different from known structures, which will occupy the same positions of the structurally conserved regions. Arranged to get the structural sequence diagram of the aspartic protease.

Homologous proteins have similar spatial folding patterns and similar biological functions. Because the spatial structure of proteins is more conservative than that of sequences in evolution, sometimes two proteins with a certain sequence difference are still homologous. Therefore, homology can be identified based on the similarity of the spatial structure between proteins. Using the homology of proteins, using homologous proteins with known three-dimensional structure as a template can be used to model homologous proteins. This method is called homologous model building method, comparative molecular simulation method (comparative molecular modeling), homology modeling, or protein homology. Although the homologous molecular method has some errors, it is still a very practical method to obtain the three-dimensional structure of homologous proteins.

Homologous molecules: A homologous protein with a known secondary structure is used as a template. The structure of the target protein with a known sequence and a three-dimensional structure is estimated and modeled.

The basic steps of homologous source protein modeling:

(1) Report the amino acid sequence of an unknown protein. Look for one or several homologous proteins in the protein database. Use as a template for estimating and modeling unknown target proteins

(2) Display and overlap the primary sequence of the target protein and the template protein;

(3) Find structurally conserved regions of the template through structural comparison and sequence analysis;

(4) Find the unknown target molecule and the template of the known structure and divide the common secondary structure region to construct the local main chain structure of the target molecule:

(5) Connect the secondary structure fragments in the target molecule according to the known structure;

Molecular dynamics and molecular dynamics methods were used to optimize the initial model of the model to obtain the structure of the unknown protein.

Software for homologous protein modeling is available from many companies, such as Homology from MSI, Consensus from Biosym, Composer from Tripos, and Insight II, Modeler.

Creative Biolabs provides professional antibody modeling assessment services for antibody modeling. With the company’s most devoted scientists, it is confident to deliver researchers the comprehensive and professional assessment to meet various project development.

Antibody Homology Model

The three-dimensional (3D) structure of antibodies offers an understanding of their function and evolution, and assists in drug design and optimization. When an experimental structure is unavailable, the antibody’s 3D structure is usually obtained through comparative modeling, also known as homology modeling, as well as via de novo computational methods. Commonly, there are four steps to construct a homology model: template selection, template–target sequence alignment, model building, and model evaluation. Besides, many sequence alignment tools and protein structure databases are available to meet the task, such as the Protein Data Bank (PDB), which has more than 1000 crystal structures of antibody fragments (Fab or Fv).
publié le lundi 13 janvier à 12:57, aucun commentaire.

Anti-cancer Breakthrough-CD47 Antibody Immunotherapy

Six scientists from the U.S. City of Hope Comprehensive Cancer Center and others detailed the progress made in identifying phagocytosis checkpoints over the past 20 years and the clinical support for the use of phagocytosis checkpoint blockage in cancer treatment Pre and early clinical evidence.

Phagocytosis checkpoint

The CD47-SIRPα axis is the first tumor phagocytosis checkpoint to be discovered. Other checkpoints involved in regulating tumor cell phagocytosis clearance and escape include the PD-1-PD-L1 axis and the MHC-I-LILRB1 axis.

CD47-SIRPα axis

SIRPα, called signal-regulatory protein α, is the first member of the SIRP family. It was identified in the late 1990s and expressed on myeloid cells, including all types of macrophages. The interaction between cd47 antibody and SIRPα was first discovered in 1999, and a large number of studies have confirmed that CD47 is widely expressed on the surface of normal cells. By binding to SIRPα on the surface of macrophages, it releases a signal of "don't eat me" This protects healthy cells from being "eaten" by macrophages. Cancer cells have also learned this mechanism: CD47 is overexpressed on the surface, causing macrophages to treat them as "normal cells," thereby evading macrophage-mediated phagocytic attacks.

Bridging innate and adaptive immunity

Antigen specific T cell response

Although the initial antitumor effect of checkpoints using CD47 to block phagocytosis was largely due to the direct clearance of tumor cells by phagocytes, there is growing evidence that the adaptive immune system, especially CD8 + T The cellular response also plays a crucial role in the antitumor effect of CD47 antibodies (Figure 3). For example, in 2015, a study published in Nature Medicine confirmed that CD47 blockade triggered T cell-mediated immunogenic tumor destruction. In 2016, a study published on PNAS confirmed that CD47 blocks adaptive antitumor response by adaptive immune stimulation: targeting CD47 and mouse melanoma antigens in a homologous B16F10 melanoma mouse model The tyrosinase-associated protein 1 (TRP-1) antibody works in synergy with PD-L1 antibody to produce a durable antitumor response, which cannot be achieved with anti cd47 antibody monotherapy or combined with TRP-1 antibody.

Targeted phagocytosis checkpoint

The CD47-SIRPα axis is the most thorough checkpoint for phagocytosis that has been studied in the cancer field. Therapies that target the CD47-SIRPα axis are now being investigated clinically for the treatment of a variety of human cancers (Table 1). Studies have shown that blocking the CD47-SIRPα interaction can lead to phagocytosis against cancer cells, and this blocking can be achieved in a variety of ways, including 1) using CD47 or SI47 targeting SI47 binding sites to block their interaction or SIRPα antibody; 2) the use of recombinant protein composed of CD47 or SIRPα extracellular region (the role is to compete with endogenous proteins, affect the normal binding of CD47 and SIRPα;); 3) use targeted regulation CD47 transcription and / or transport pathway drugs to inhibit the expression of CD47 on the surface of cancer cells.

At present, phagocytosis checkpoint blocking, especially the treatment of CD47-SIRPα axis, has proven to be a promising therapy in both hematological and solid malignancies, with acceptable safety and toxicity characteristics. . Next, larger clinical studies and longer follow-up periods are needed to validate current findings. Whether targeting other phagocytosis checkpoints can produce similar therapeutic benefits remains to be seen.
publié le dimanche 12 janvier à 06:30, aucun commentaire.

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