Rational Design and Identification of Small‐Molecule Allosteric Inhibitors of CD38

Yang, Lixin; Li, Ting; Li, Songlu; Wu, Yang Chang; Shi, Xiaomeng; Jin, Hongwei; Liu, Zhenming; Zhao, Yong; Zhang, Liangren; Lee, Hon Cheung; Zhang, Lihe

doi:10.1002/cbic.201900169

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…The inflammatory conditions and the status of macrophages have been monitored using two types of CD38 inhibitor molecules. The first (kuromanin, apigenin, and rhein) originates from the flavonoid and anthraquinone families (174,175), while the second (LX102) is a specifically designed chemical compound (176). When applied to explore the functional role of CD38 in macrophages, these treatments suppressed the IL-6 and IL-12 molecules, as well as pathways such as NF-κB, P2Rs, caspase-1, and ERK1/2, all of which are involved in the promotion of inflammation by CD38 (71,177).…”

Section: Cd38 Expression and Regulation Of Intracellular Ca 21 Storesmentioning

confidence: 99%

CD38 in the age of COVID-19: a medical perspective

Horenstein

Faini

Malavasi

2021

Physiological Reviews

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This medical review addresses the hypothesis that CD38/NADase is at the center of a functional axis (i.e., intracellular Ca2+ mobilization/IFNɣ response/ROS burst) driven by SARS-CoV-2 infection, as already verified in Respiratory Syncytial Virus pathology and CD38 activity in other cellular settings. Key features of the hypothesis are that: i) the substrates of CD38 (e.g., NAD+ and NADP+) are depleted by viral-induced metabolic changes; ii) the products of the enzymatic activity of CD38 (e.g., cADPR/ADPR/NAADP) and related enzymes (e.g., PARPs, Sirtuins, ADP-ribosyl hydrolase) are involved in the anti‐viral and proinflammatory response that favors the onset of lung immunopathology (e.g., cytokine storm and organ fibrosis); and iii) the pathological changes induced by this kinetic mechanism may be reduced by distinct modulators of the CD38/NAD+ axis (e.g., CD38 blockers; NAD+ suppliers, among others). This view is supported by arrays of associative basic and applied research data which are herein discussed and integrated with conclusions reported by others in the field of inflammatory, immune, tumor and viral diseases.

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Section: Cd38 Expression and Regulation Of Intracellular Ca 21 Storesmentioning

confidence: 99%

CD38 in the age of COVID-19: a medical perspective

Horenstein

Faini

Malavasi

2021

Physiological Reviews

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“…Subsequently, AlloFinder was used to identify the allosteric site and modulators for the surface antigen CD38. The allosteric modulator LX-102 was found to target CD38 on the side opposite its enzymatic binding pocket, with this confirmed by surface plasmon resonance (SPR) and HDX-MS experiments [107].…”

Section: Perspective Of Novel Pxr Allosteric Binding Sitesmentioning

confidence: 78%

Allosteric Antagonism of the Pregnane X Receptor (PXR): Current-State-of-the-Art and Prediction of Novel Allosteric Sites

Kamaraj

Drastík

Maixnerová

et al. 2022

Cells

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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-activated transcription factor with high levels of expression in the liver. It not only plays a key role in drug metabolism and elimination, but also promotes tumor growth, drug resistance, and metabolic diseases. It has been proposed as a therapeutic target for type II diabetes, metabolic syndrome, and inflammatory bowel disease, and PXR antagonists have recently been considered as a therapy for colon cancer. There are currently no PXR antagonists that can be used in a clinical setting. Nevertheless, due to the large and complex ligand-binding pocket (LBP) of the PXR, it is challenging to discover PXR antagonists at the orthosteric site. Alternative ligand binding sites of the PXR have also been proposed and are currently being studied. Recently, the AF-2 allosteric binding site of the PXR has been identified, with several compounds modulating the site discovered. Herein, we aimed to summarize our current knowledge of allosteric modulation of the PXR as well as our attempt to unlock novel allosteric sites. We describe the novel binding function 3 (BF-3) site of PXR, which is also common for other nuclear receptors. In addition, we also mention a novel allosteric site III based on in silico prediction. The identified allosteric sites of the PXR provide new insights into the development of safe and efficient allosteric modulators of the PXR receptor. We therefore propose that novel PXR allosteric sites might be promising targets for treating chronic metabolic diseases and some cancers.

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“…A fourth peptide was suggested based on the binding site of a small-molecule LX-102 that competes with isatuximab. 29 The constructs were named CD38_F12_m1, CD38_F12_m2, CD38_F12_m3, and CD38_F12_m4. The numbering of the mutations corresponds to the sequence of the structural template PDB:2O3S.…”

Section: Resultsmentioning

confidence: 99%

“… 32–36 Although extracellular NAD+ is present in low amounts, recent studies show that mammalian cells can import low concentrations of NAD+ across the membrane. 29 , 37–39 This suggests that an unidentified transporter of intact NAD+ might exist. 40 The mechanism of direct import of NAD+ into the cells has yet to be ascertained.…”

Section: Discussionmentioning

confidence: 99%

TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity

Ugamraj

Dang

Ouisse

et al. 2022

mAbs

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Cluster of differentiation 38 (CD38) is an ecto-enzyme expressed primarily on immune cells that metabolize nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose or cyclic ADP-ribose and nicotinamide. Other substrates of CD38 include nicotinamide adenine dinucleotide phosphate and nicotinamide mononucleotide, a critical NAD+ precursor in the salvage pathway. NAD+ is an important coenzyme involved in several metabolic pathways and is a required cofactor for the function of sirtuins (SIRTs) and poly (adenosine diphosphate-ribose) polymerases. Declines in NAD+ levels are associated with metabolic and inflammatory diseases, aging, and neurodegenerative disorders. To inhibit CD38 enzyme activity and boost NAD+ levels, we developed TNB-738, an anti-CD38 biparatopic antibody that pairs two non-competing heavy chain-only antibodies in a bispecific format. By simultaneously binding two distinct epitopes on CD38, TNB-738 potently inhibited its enzymatic activity, which in turn boosted intracellular NAD+ levels and SIRT activities. Due to its silenced IgG4 Fc, TNB-738 did not deplete CD38-expressing cells, in contrast to the clinically available anti-CD38 antibodies, daratumumab, and isatuximab. TNB-738 offers numerous advantages compared to other NAD-boosting therapeutics, including small molecules, and supplements, due to its long half-life, specificity, safety profile, and activity. Overall, TNB-738 represents a novel treatment with broad therapeutic potential for metabolic and inflammatory diseases associated with NAD+ deficiencies. Abbreviations: 7-AAD: 7-aminoactinomycin D; ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody dependent cell-mediated phagocytosis; ADPR: adenosine diphosphate ribose; APC: allophycocyanin; cADPR: cyclic ADP-ribose; cDNA: complementary DNA; BSA: bovine serum albumin; CD38: cluster of differentiation 38; CDC: complement dependent cytotoxicity; CFA: Freund’s complete adjuvant; CHO: Chinese hamster ovary; CCP4: collaborative computational project, number 4; COOT: crystallographic object-oriented toolkit; DAPI: 4′,6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; DSC: differential scanning calorimetry; 3D: three dimensional; εNAD+: nicotinamide 1,N 6 -ethenoadenine dinucleotide; ECD: extracellular domain; EGF: epidermal growth factor; FACS: fluorescence activated cell sorting; FcγR: Fc gamma receptors; FITC: fluorescein isothiocyanate; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; IgG: immunoglobulin; IFA: incomplete Freund’s adjuvant; IFNγ: Interferon gamma; KB: kinetic buffer; kDa: kilodalton; KEGG: kyoto encyclopedia of genes and genomes; LDH: lactate dehydrogenase; M: molar; mM: millimolar; MFI: mean fluorescent intensity; NA: nicotinic acid; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; NAM: nicotinamide; NGS: next-generation sequencing; NHS/EDC: N-Hydroxysuccinimide/ ethyl (dimethylamino pro...

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Rational Design and Identification of Small‐Molecule Allosteric Inhibitors of CD38

Cited by 6 publications

References 24 publications

CD38 in the age of COVID-19: a medical perspective

CD38 in the age of COVID-19: a medical perspective

Allosteric Antagonism of the Pregnane X Receptor (PXR): Current-State-of-the-Art and Prediction of Novel Allosteric Sites

TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity

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