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1.
Mol Pharm ; 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38958508

ABSTRACT

Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale and to be used for drug delivery via high-concentration formulations. Crystalline mAb suspensions are expected to have enhanced chemical and physical properties relative to mAb solutions delivered intravenously, making them attractive candidates for subcutaneous delivery. In contrast to small molecules, the development of protein crystalline suspensions is not a widely used approach in the pharmaceutical industry. This is mainly due to the challenges in finding crystalline hits and the suboptimal physical properties of the resulting crystallites when hits are found. Modern advances in instrumentation and increased knowledge of mAb crystallization have, however, resulted in higher probabilities of discovering crystal forms and improving their particle properties and characterization. In this regard, physical, analytical characterization plays a central role in the initial steps of understanding and later optimizing the crystallization of mAbs and requires careful selection of the appropriate tools. This contribution describes a novel crystal structure of the antibody pembrolizumab and demonstrates the usefulness of small-angle X-ray scattering (SAXS) for characterizing its crystalline suspensions. It illustrates the advantages of SAXS when used to (i) confirm crystallinity and crystal phase of crystallites produced in batch mode; (ii) confirm crystallinity under various conditions and detect variations in crystal phases, enabling fine-tuning of the crystallizations for phase control across multiple batches; (iii) monitor the physical response and stability of the crystallites in suspension with regard to filtration and washing; and (iv) monitor the physical stability of the crystallites upon drying. Overall, this work highlights how SAXS is an essential tool for mAb crystallization characterization.

2.
iScience ; 26(8): 107452, 2023 Aug 18.
Article in English | MEDLINE | ID: mdl-37593455

ABSTRACT

The fast pace of breakthroughs in cancer immunotherapy, combined with the new paradigm of moving toward high-concentration dosages and combinatorial treatments, is generating new challenges in the formulation of biologics. To address these challenges, we describe a method of formulation that enables high-concentration injectable and stable formulation of biologics as amorphous solids in aqueous suspension. This technology combines the benefits of liquid formulation with the stability of solid formulation and eliminates the need for drying and reconstitution. This widely applicable formulation integrates the amorphous solid forms of antibodies with the injectability, lubricity, and tunability of soft alginate hydrogel particles using a minimal process. The platform was evaluated for anti-PD-1 antibody pembrolizumab and human immunoglobulin G at concentrations up to 300 mg/mL with confirmed quality after release. The soft nature of the hydrogel matrix allowed packing the particles to high volume fractions.

3.
Adv Healthc Mater ; 12(15): e2202370, 2023 06.
Article in English | MEDLINE | ID: mdl-36745878

ABSTRACT

Subcutaneous (SC) administration is a desired route for monoclonal antibodies (mAbs). However, formulating mAbs for small injection volumes at high concentrations with suitable stability and injectability is a significant challenge. Here, this work presents a platform technology that combines the stability of crystalline antibodies with injectability and tunability of soft hydrogel particles. Composite alginate hydrogel particles are generated via a gentle centrifugal encapsulation process which avoids use of chemical reactions or an external organic phase. Crystalline suspension of anti-programmed cell death protein 1 (PD-1) antibody (pembrolizumab) is utilized as a model therapeutic antibody. Crystalline forms of the mAb encapsuled in the hydrogel particles lead to stable, high concentration, and injectable formulations. Formulation concentrations as high as 315 mg mL-1 antibody are achieved with encapsulation efficiencies in the range of 89-97%, with no perceivable increase in the number of antibody aggregates. Bioanalytical studies confirm superior maintained quality of the antibody in comparison with formulation approaches involving organic phases and chemical reactions. This work illustrates tuning the alginate particles' disintegration by using partially oxide alginates. Crystalline mAb-laden particles are evaluated for their biocompatibility using cell-based in vitro assays. Furthermore, the pharmacokinetics (PK) of the subcutaneously delivered human anti-PD-1 mAb in crystalline antibody-laden alginate hydrogel particles in Wistar rats is evaluated.


Subject(s)
Alginates , Antibodies, Monoclonal , Rats , Animals , Humans , Alginates/chemistry , Rats, Wistar , Antibodies, Monoclonal/pharmacokinetics , Subcutaneous Tissue/metabolism , Hydrogels/chemistry
4.
Mol Pharm ; 19(3): 936-952, 2022 03 07.
Article in English | MEDLINE | ID: mdl-35107019

ABSTRACT

Developing biological formulations to maintain the chemical and structural integrity of therapeutic antibodies remains a significant challenge. Monoclonal antibody (mAb) crystalline suspension formulation is a promising alternative for high concentration subcutaneous drug delivery. It demonstrates many merits compared to the solution formulation to reach a high concentration at the reduced viscosity and enhanced stability. One main challenge in drug development is the lack of high-resolution characterization of the crystallinity and stability of mAb microcrystals in the native formulations. Conventional analytical techniques often cannot evaluate structural details of mAb microcrystals in the native suspension due to the presence of visible particles, relatively small crystal size, high protein concentration, and multicomponent nature of a liquid formulation. This study demonstrates the first high-resolution characterization of mAb microcrystalline suspension using magic angle spinning (MAS) NMR spectroscopy. Crystalline suspension formulation of pembrolizumab (Keytruda, Merck & Co., Inc., Kenilworth, NJ 07033, U.S.) is utilized as a model system. Remarkably narrow 13C spectral linewidth of approximately 29 Hz suggests a high order of crystallinity and conformational homogeneity of pembrolizumab crystals. The impact of thermal stress and dehydration on the structure, dynamics, and stability of these mAb crystals in the formulation environment is evaluated. Moreover, isotopic labeling and heteronuclear 13C and 15N spectroscopies have been utilized to identify the binding of caffeine in the pembrolizumab crystal lattice, providing molecular insights into the cocrystallization of the protein and ligand. Our study provides valuable structural details for facilitating the design of crystalline suspension formulation of Keytruda and demonstrates the high potential of MAS NMR as an advanced tool for biophysical characterization of biological therapeutics.


Subject(s)
Antibodies, Monoclonal, Humanized , Proteins , Magnetic Resonance Spectroscopy , Molecular Conformation , Proteins/chemistry , Suspensions
5.
Bioorg Med Chem Lett ; 30(15): 127279, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32527459

ABSTRACT

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.


Subject(s)
Drug Discovery , Factor IXa/antagonists & inhibitors , Factor Xa Inhibitors/pharmacology , Pyrimidines/pharmacology , Dose-Response Relationship, Drug , Factor IXa/metabolism , Factor Xa Inhibitors/chemical synthesis , Factor Xa Inhibitors/chemistry , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
6.
NPJ Microgravity ; 5: 28, 2019.
Article in English | MEDLINE | ID: mdl-31815178

ABSTRACT

Crystallization processes have been widely used in the pharmaceutical industry for the manufacture, storage, and delivery of small-molecule and small protein therapeutics. However, the identification of crystallization processes for biologics, particularly monoclonal antibodies, has been prohibitive due to the size and the flexibility of their overall structure. There remains a challenge and an opportunity to utilize the benefits of crystallization of biologics. The research laboratories of Merck Sharp & Dome Corp. (MSD) in collaboration with the International Space Station (ISS) National Laboratory performed crystallization experiments with pembrolizumab (Keytruda®) on the SpaceX-Commercial Resupply Services-10 mission to the ISS. By leveraging microgravity effects such as reduced sedimentation and minimal convection currents, conditions producing crystalline suspensions of homogeneous monomodal particle size distribution (39 µm) in high yield were identified. In contrast, the control ground experiments produced crystalline suspensions with a heterogeneous bimodal distribution of 13 and 102 µm particles. In addition, the flight crystalline suspensions were less viscous and sedimented more uniformly than the comparable ground-based crystalline suspensions. These results have been applied to the production of crystalline suspensions on earth, using rotational mixers to reduce sedimentation and temperature gradients to induce and control crystallization. Using these techniques, we have been able to produce uniform crystalline suspensions (1-5 µm) with acceptable viscosity (<12 cP), rheological, and syringeability properties suitable for the preparation of an injectable formulation. The results of these studies may help widen the drug delivery options to improve the safety, adherence, and quality of life for patients and caregivers.

8.
ACS Med Chem Lett ; 7(3): 324-9, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26985323

ABSTRACT

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

9.
Nat Struct Mol Biol ; 22(12): 953-8, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26595420

ABSTRACT

Immunoglobulin G4 antibodies exhibit unusual properties with important biological consequences. We report the structure of the human full-length IgG4 S228P anti-PD1 antibody pembrolizumab, solved to 2.3-Å resolution. Pembrolizumab is a compact molecule, consistent with the presence of a short hinge region. The Fc domain is glycosylated at the CH2 domain on both chains, but one CH2 domain is rotated 120° with respect to the conformation observed in all reported structures to date, and its glycan chain faces the solvent. We speculate that this new conformation is driven by the shorter hinge. The structure suggests a role for the S228P mutation in preventing the IgG4 arm exchange. In addition, this unusual Fc conformation suggests possible structural diversity between IgG subclasses and shows that use of isolated antibody fragments could mask potentially important interactions, owing to molecular flexibility.


Subject(s)
Antibodies, Monoclonal, Humanized/chemistry , Antineoplastic Agents/chemistry , Immunoglobulin G/chemistry , Programmed Cell Death 1 Receptor/immunology , Crystallography, X-Ray , Humans , Protein Conformation , Protein Structure, Tertiary
10.
Bioorg Med Chem Lett ; 25(22): 5437-43, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26318999

ABSTRACT

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.


Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Factor IXa/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemical synthesis , Humans , Molecular Structure , Rats
11.
Bioorg Med Chem Lett ; 25(11): 2321-5, 2015 Jun 01.
Article in English | MEDLINE | ID: mdl-25937013

ABSTRACT

Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 µM to 0.016 µM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 µM to 0.09 µM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.


Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor IXa/antagonists & inhibitors , Binding Sites , Drug Discovery , Humans , Models, Molecular , Molecular Structure , Protein Conformation
12.
Bioorg Med Chem Lett ; 25(21): 4945-4949, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-25978966

ABSTRACT

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.


Subject(s)
Amines/pharmacology , Enzyme Inhibitors/pharmacology , Factor IXa/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/chemistry , Animals , Biological Availability , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Factor IXa/metabolism , Humans , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship
13.
J Biol Chem ; 289(26): 18008-21, 2014 Jun 27.
Article in English | MEDLINE | ID: mdl-24821719

ABSTRACT

The symptoms of Clostridium difficile infections are caused by two exotoxins, TcdA and TcdB, which target host colonocytes by binding to unknown cell surface receptors, at least in part via their combined repetitive oligopeptide (CROP) domains. A combination of the anti-TcdA antibody actoxumab and the anti-TcdB antibody bezlotoxumab is currently under development for the prevention of recurrent C. difficile infections. We demonstrate here through various biophysical approaches that bezlotoxumab binds to specific regions within the N-terminal half of the TcdB CROP domain. Based on this information, we solved the x-ray structure of the N-terminal half of the TcdB CROP domain bound to Fab fragments of bezlotoxumab. The structure reveals that the TcdB CROP domain adopts a ß-solenoid fold consisting of long and short repeats and that bezlotoxumab binds to two homologous sites within the CROP domain, partially occluding two of the four putative carbohydrate binding pockets located in TcdB. We also show that bezlotoxumab neutralizes TcdB by blocking binding of TcdB to mammalian cells. Overall, our data are consistent with a model wherein a single molecule of bezlotoxumab neutralizes TcdB by binding via its two Fab regions to two epitopes within the N-terminal half of the TcdB CROP domain, partially blocking the carbohydrate binding pockets of the toxin and preventing toxin binding to host cells.


Subject(s)
Antibodies, Bacterial/immunology , Antibodies, Neutralizing/immunology , Bacterial Proteins/chemistry , Bacterial Proteins/immunology , Bacterial Toxins/chemistry , Bacterial Toxins/immunology , Clostridioides difficile/immunology , Epitopes/immunology , Amino Acid Sequence , Antibodies, Bacterial/chemistry , Antibodies, Monoclonal , Antibodies, Neutralizing/chemistry , Bacterial Proteins/genetics , Bacterial Toxins/genetics , Binding Sites , Broadly Neutralizing Antibodies , Clostridioides difficile/chemistry , Clostridioides difficile/genetics , Crystallography, X-Ray , Epitope Mapping , Epitopes/chemistry , Epitopes/genetics , Models, Molecular , Molecular Sequence Data , Protein Structure, Tertiary
14.
J Mass Spectrom ; 45(12): 1416-25, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21053369

ABSTRACT

Interleukin-23 (IL-23) is a heterodimeric cytokine, a central factor in chronic/autoimmune inflammation. It signals through a heterodimeric receptor consisting of IL-23r, which is heavily glycosylated. The structural characterization of IL-23r has not been reported. In this work, glycosylation profiles of soluble recombinant human IL-23r (rhIL-23r) were established using mass spectrometry (MS), which included defining glycosylation sites, degree of glycosylation occupancy of each site and structure of attached oligosaccharides. Specifically, precursor ion scan of oxonium ion protonated N-acetylglucosamine (GlcNAc(+)) (m/z 204) was performed using a triple quadrupole MS instrument to locate the retention time of glycopeptides. Both the glycopeptides and their corresponding deglycosylated forms in each collected HPLC fraction were studied by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (LTQ-Orbitrap) for glycosylation site profiling. The attached glycan structures were elucidated by collision-induced dissociation (CID) fragmentation of target glycopeptides in combination with accurate mass measurement. Eight glycosylation sites were identified on IL-23r (Asn24, Asn209, Asn239, Asn157, Asn118, Asn250, Asn58 and Asn6). Most of the glycosylation sites were > 95% occupied except Asn250 and Asn6. Those two sites were 88% and 45% occupied by estimation from trypsin digestion and were 55% and 42% occupied from LysC digestion. Multiple glycoforms were observed in IL-23r. Most of them were bi-, tri- or tetra-antennary complex type structures with fucose and sialic acid. High mannose and hybrid type glycans were only observed on Asn157. The structural characterization on IL-23r glycosylation provides useful information for better understanding of the biological function of IL-23r.


Subject(s)
Polysaccharides/chemistry , Polysaccharides/metabolism , Receptors, Interleukin/chemistry , Receptors, Interleukin/metabolism , Acetylglucosamine/chemistry , Acetylglucosamine/metabolism , Amino Acid Sequence , Carbohydrate Conformation , Chromatography, High Pressure Liquid , Glycopeptides/chemistry , Glycopeptides/metabolism , Glycosylation , Humans , Molecular Sequence Data , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Tandem Mass Spectrometry
15.
Biochemistry ; 48(12): 2661-74, 2009 Mar 31.
Article in English | MEDLINE | ID: mdl-19161339

ABSTRACT

MEK1 is a member of the MAPK signal transduction pathway that responds to growth factors and cytokines. We have determined that the kinase domain spans residues 35-382 by proteolytic cleavage. The complete kinase domain has been crystallized and its X-ray crystal structure as a complex with magnesium and ATP-gammaS determined at 2.1 A. Unlike crystals of a truncated kinase domain previously published, the crystals of the intact domain can be grown either as a binary complex with a nucleotide or as a ternary complex with a nucleotide and one of a multitude of allosteric inhibitors. Further, the crystals allow for the determination of costructures with ATP competitive inhibitors. We describe the structures of nonphosphorylated MEK1 (npMEK1) binary complexes with ADP and K252a, an ATP-competitive inhibitor (see Table 1), at 1.9 and 2.7 A resolution, respectively. Ternary complexes have also been solved between npMEK1, a nucleotide, and an allosteric non-ATP competitive inhibitor: ATP-gammaS with compound 1 and ADP with either U0126 or the MEK1 clinical candidate PD325089 at 1.8, 2.0, and 2.5 A, respectively. Compound 1 is structurally similar to PD325901. These structures illustrate fundamental differences among various mechanisms of inhibition at the molecular level. Residues 44-51 have previously been shown to play a negative regulatory role in MEK1 activity. The crystal structure of the integral kinase domain provides a structural rationale for the role of these residues. They form helix A and repress enzymatic activity by stabilizing an inactive conformation in which helix C is displaced from its active state position. Finally, the structure provides for the first time a molecular rationale that explains how mutations in MEK may lead to the cardio-facio-cutaneous syndrome.


Subject(s)
Enzyme Inhibitors/chemistry , MAP Kinase Kinase 1/chemistry , Nucleotides/chemistry , Adenosine Diphosphate/chemistry , Adenosine Diphosphate/metabolism , Allosteric Regulation , Binding Sites , Carbazoles/chemistry , Carbazoles/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/metabolism , Indole Alkaloids/chemistry , Indole Alkaloids/metabolism , MAP Kinase Kinase 1/metabolism , Models, Molecular , Nucleotides/metabolism , Protein Conformation , Structure-Activity Relationship , Substrate Specificity
16.
J Mol Biol ; 382(4): 942-55, 2008 Oct 17.
Article in English | MEDLINE | ID: mdl-18708069

ABSTRACT

Interleukin (IL)-23 is a pro-inflammatory cytokine playing a key role in the pathogenesis of several autoimmune and inflammatory diseases. We have determined the crystal structures of the heterodimeric p19-p40 IL-23 and its complex with the Fab (antigen-binding fragment) of a neutralizing antibody at 2.9 and 1.9 A, respectively. The IL-23 structure closely resembles that of IL-12. They share the common p40 subunit, and IL-23 p19 overlaps well with IL-12 p35. Along the hydrophilic heterodimeric interface, fewer charged residues are involved for IL-23 compared with IL-12. The binding site of the Fab is located exclusively on the p19 subunit, and comparison with published cytokine-receptor structures suggests that it overlaps with the IL-23 receptor binding site.


Subject(s)
Antibodies, Monoclonal/chemistry , Immunoglobulin Fab Fragments/chemistry , Inflammation/immunology , Interleukin-12 Subunit p40/chemistry , Interleukin-23 Subunit p19/chemistry , Protein Conformation , Amino Acid Sequence , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Binding Sites , Crystallography, X-Ray , Dimerization , Humans , Immunoglobulin Fab Fragments/genetics , Immunoglobulin Fab Fragments/immunology , Interleukin-12 Subunit p40/genetics , Interleukin-12 Subunit p40/immunology , Interleukin-23 Subunit p19/genetics , Interleukin-23 Subunit p19/immunology , Models, Molecular , Molecular Sequence Data , Receptors, Cytokine/chemistry , Receptors, Cytokine/metabolism , Receptors, Interleukin/chemistry , Receptors, Interleukin/genetics , Receptors, Interleukin/immunology
18.
Biochim Biophys Acta ; 1698(2): 255-9, 2004 May 06.
Article in English | MEDLINE | ID: mdl-15134659

ABSTRACT

Human beta-amyloid precursor protein cleaving enzyme (beta-secretase, or BACE) belongs to the aspartyl protease family, and is responsible for generating the N-terminus of beta-amyloid peptide (Abeta). BACE is a type I transmembrane glycoprotein with pre-, pro- and catalytic domains, a short transmembrane helix and a cytoplasmic region. In this study, a truncated form was engineered to produce the authentic catalytic domain of BACE in Trichoplusia ni (High 5) cells. The glycosylated BACE zymogen (proBACE) was secreted into the conditioned medium for facile purification by metal chelate and gel filtration chromatographies. The mature catalytic domain was obtained by a trans cleavage event under acidic conditions and crystallized in the absence of a bound inhibitor. A complete 3.4 A data set was collected on a single orthorhombic crystal with unit cell parameters a=74 A, b=130 A, c=134A. Successful molecular replacement shows two BACE molecules in the asymmetric unit.


Subject(s)
Aspartic Acid Endopeptidases/chemistry , Peptides/chemistry , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Cells, Cultured , Cloning, Molecular , Crystallization , Endopeptidases , Humans , Moths/genetics , Moths/metabolism , Peptides/genetics , Peptides/metabolism , Protein Structure, Tertiary
19.
J Mol Biol ; 335(1): 129-37, 2004 Jan 02.
Article in English | MEDLINE | ID: mdl-14659745

ABSTRACT

Adam33 is a putative asthma susceptibility gene encoding for a membrane-anchored metalloprotease belonging to the ADAM family. The ADAMs (a disintegrin and metalloprotease) are a family of glycoproteins implicated in cell-cell interactions, cell fusion, and cell signaling. We have determined the crystal structure of the Adam33 catalytic domain in complex with the inhibitor marimastat and the inhibitor-free form. The structures reveal the polypeptide fold and active site environment resembling that of other metalloproteases. The substrate-binding site contains unique features that allow the structure-based design of specific inhibitors of this enzyme.


Subject(s)
Catalytic Domain , Crystallography, X-Ray , Metalloendopeptidases/chemistry , ADAM Proteins , Amino Acid Sequence , Enzyme Inhibitors/chemistry , Humans , Hydroxamic Acids/chemistry , Metalloendopeptidases/genetics , Models, Molecular , Molecular Structure , Mutation , Protein Binding , Protein Structure, Tertiary , Sequence Alignment
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