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Article ; Online: CD40-targeting KGYY

Bojadzic, Damir / Buchwald, Peter

2019 Volume 62, Issue 11, Page(s) 2158–2160

MeSH term(s)	Animals ; CD40 Antigens/antagonists & inhibitors ; CD40 Antigens/metabolism ; CD40 Ligand/antagonists & inhibitors ; CD40 Ligand/metabolism ; Cell Line ; Diabetes Mellitus, Type 1/drug therapy ; Disease Models, Animal ; Humans ; Hyperglycemia/metabolism ; Inhibitory Concentration 50 ; Mice ; Peptides/pharmacology
Chemical Substances	CD40 Antigens ; Peptides ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2019-09-09
Publishing country	Germany
Document type	Letter
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-019-04996-6
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Article: Methylene Blue Inhibits the SARS-CoV-2 Spike-ACE2 Protein-Protein Interaction-a Mechanism that can Contribute to its Antiviral Activity Against COVID-19.

Bojadzic, Damir / Alcazar, Oscar / Buchwald, Peter

Frontiers in pharmacology

2021 Volume 11, Page(s) 600372

Abstract: Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction ... ...

Abstract	Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC
Language	English
Publishing date	2021-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.600372
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Article ; Online: Toward Small-Molecule Inhibition of Protein-Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions.

Bojadzic, Damir / Buchwald, Peter

Current topics in medicinal chemistry

2018 Volume 18, Issue 8, Page(s) 674–699

Abstract: Protein-Protein Interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have ... ...

Abstract	Protein-Protein Interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable. Nevertheless, substantial progress has been achieved during the last decade. SMPPIIs proving the feasibility of such approaches have been identified through various strategies for a number of cosignaling interactions including CD40-CD40L, OX40-OX40L, BAFFR-BAFF, CD80-CD28, and PD-1-PD-L1s. Here, after an overview of the general aspects and challenges of SMPPII-focused drug discovery, we review them briefly together with relevant structural, immune-signaling, physicochemical, and medicinal chemistry aspects. While so far only a few of these SMPPIIs have shown activity in animal models (DRI-C21045 for CD40-D40L, KR33426 for BAFFR-BAFF) or reached clinical development (RhuDex for CD80-CD28, CA-170 for PD-1-PD-L1), there is proof-of-principle evidence for the feasibility of such approaches in immunomodulation. They can result in products that are easier to develop/ manufacture and are less likely to be immunogenic or encounter postmarket safety events than corresponding biologics, and, contrary to them, can even become orally bioavailable.
MeSH term(s)	Animals ; Drug Discovery ; Humans ; Molecular Conformation ; Protein Binding/drug effects ; Proteins/antagonists & inhibitors ; Proteins/chemistry ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	Proteins ; Small Molecule Libraries
Language	English
Publishing date	2018-07-31
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/1568026618666180531092503
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Book ; Online: Non-Holonomic RRT & MPC

Bojadžić, Damir / Kunze, Julian / Osmanković, Dinko / Malmir, Mohammadhossein / Knoll, Alois

Path and Trajectory Planning for an Autonomous Cycle Rickshaw

2021

Abstract: This paper presents a novel hierarchical motion planning approach based on Rapidly-Exploring Random Trees (RRT) for global planning and Model Predictive Control (MPC) for local planning. The approach targets a three-wheeled cycle rickshaw (trishaw) used ... ...

Abstract	This paper presents a novel hierarchical motion planning approach based on Rapidly-Exploring Random Trees (RRT) for global planning and Model Predictive Control (MPC) for local planning. The approach targets a three-wheeled cycle rickshaw (trishaw) used for autonomous urban transportation in shared spaces. Due to the nature of the vehicle, the algorithms had to be adapted in order to adhere to non-holonomic kinematic constraints using the Kinematic Single-Track Model. The vehicle is designed to offer transportation for people and goods in shared environments such as roads, sidewalks, bicycle lanes but also open spaces that are often occupied by other traffic participants. Therefore, the algorithm presented in this paper needs to anticipate and avoid dynamic obstacles, such as pedestrians or bicycles, but also be fast enough in order to work in real-time so that it can adapt to changes in the environment. Our approach uses an RRT variant for global planning that has been modified for single-track kinematics and improved by exploiting dead-end nodes. This allows us to compute global paths in unstructured environments very fast. In a second step, our MPC-based local planner makes use of the global path to compute the vehicle's trajectory while incorporating dynamic obstacles such as pedestrians and other road users. Our approach has shown to work both in simulation as well as first real-life tests and can be easily extended for more sophisticated behaviors. Comment: Submitted to IROS 2021, 6 pages, 4 figures
Keywords	Computer Science - Robotics
Subject code	629
Publishing date	2021-03-10
Publishing country	us
Document type	Book ; Online
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Article ; Online: Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40⁻CD154 Costimulatory Protein-Protein Interaction.

Bojadzic, Damir / Chen, Jinshui / Alcazar, Oscar / Buchwald, Peter

Molecules (Basel, Switzerland)

2018 Volume 23, Issue 5

Abstract: We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40⁻CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory ... ...

Abstract	We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40⁻CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory interaction that is an important therapeutic target since it plays crucial roles in the activation of T cell responses, and there is resurgent interest in its modulation with several biologics in development. However, this interaction, just as all other PPIs, is difficult to target by small molecules. Following up on our previous work, we have now identified novel compounds such as DRI-C21091 or DRI-C21095 that show activity (IC
MeSH term(s)	Animals ; CD40 Antigens/chemistry ; CD40 Antigens/metabolism ; CD40 Ligand/chemistry ; CD40 Ligand/metabolism ; Cell Line ; Chemistry Techniques, Synthetic ; Drug Design ; Humans ; Immunologic Factors/chemical synthesis ; Immunologic Factors/chemistry ; Immunologic Factors/pharmacology ; Immunomodulation/drug effects ; Mice ; Models, Molecular ; Protein Binding/drug effects ; Protein Conformation ; Protein Multimerization
Chemical Substances	CD40 Antigens ; Immunologic Factors ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2018-05-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules23051153
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Article ; Online: Small-Molecule In Vitro Inhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Bojadzic, Damir / Alcazar, Oscar / Chen, Jinshui / Buchwald, Peter

bioRxiv

Abstract: Inhibitors of the protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and ACE2, which acts as a ligand-receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are ... ...

Abstract	Inhibitors of the protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and ACE2, which acts as a ligand-receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are of considerable interest as potential antiviral agents. While blockade of such PPIs with small molecules is more challenging than with antibodies, small-molecule inhibitors (SMIs) might offer alternatives that are less strain- and mutation-sensitive, suitable for oral or inhaled administration, and more controllable / less immunogenic. Here, we report the identification of SMIs of this PPI by screening our compound-library that is focused on the chemical space of organic dyes. Among promising candidates identified, several dyes (Congo red, direct violet 1, Evans blue) and novel drug-like compounds (DRI-C23041, DRI-C91005) inhibited the interaction of hACE2 with the spike proteins of SARS-CoV-2 as well as SARS-CoV with low micromolar activity in our cell-free ELISA-type assays (IC50s of 0.2-3.0 μM); whereas, control compounds, such as sunset yellow FCF, chloroquine, and suramin, showed no activity. Protein thermal shift assays indicated that the SMIs identified here bind SARS-CoV-2-S and not ACE2. Selected promising compounds inhibited the entry of a SARS-CoV-2-S expressing pseudovirus into ACE2-expressing cells in concentration-dependent manner with low micromolar IC50s (6-30 μM). This provides proof-of-principle evidence for the feasibility of small-molecule inhibition of PPIs critical for coronavirus attachment/entry and serves as a first guide in the search for SMI-based alternative antiviral therapies for the prevention and treatment of diseases caused by coronaviruses in general and COVID-19 in particular.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.10.22.351056
Database	COVID19

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Article ; Online: Methylene Blue Inhibits In Vitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction – A Mechanism That Can Contribute to Its Antiviral Activity Against COVID-19

Bojadzic, Damir / Alcazar, Oscar / Buchwald, Peter

bioRxiv

Abstract	Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction with an activity similar, possibly slightly higher, than those found for it for other PPIs. This PPI inhibitory activity of methylene blue could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.08.29.273441
Database	COVID19

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Article ; Online: Small-Molecule In Vitro Inhibitors of the Coronavirus Spike - ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Bojadzic, Damir / Alcazar, Oscar / Chen, Jinshui / Buchwald, Peter

bioRxiv

Abstract	Inhibitors of the protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and ACE2, which acts as a ligand-receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are of considerable interest as potential antiviral agents. While blockade of such PPIs with small molecules is more challenging than with antibodies, small-molecule inhibitors (SMIs) might offer alternatives that are less strain- and mutation-sensitive, suitable for oral or inhaled administration, and more controllable / less immunogenic. Here, we report the identification of SMIs of this PPI by screening our compound-library that is focused on the chemical space of organic dyes. Among promising candidates identified, several dyes (Congo red, direct violet 1, Evans blue) and novel drug-like compounds (DRI-C23041, DRI-C91005) inhibited the interaction of hACE2 with the spike proteins of SARS-CoV-2 as well as SARS-CoV with low micromolar activity in our cell-free ELISA-type assays (IC50s of 0.2-3.0 μM); whereas, control compounds, such as sunset yellow FCF, chloroquine, and suramin, showed no activity. Protein thermal shift assays indicated that the SMIs identified here bind SARS-CoV-2-S and not ACE2. Selected promising compounds inhibited the entry of a SARS-CoV-2-S expressing pseudovirus into ACE2-expressing cells in concentration-dependent manner with low micromolar IC50s (6-30 μM). This provides proof-of-principle evidence for the feasibility of small-molecule inhibition of PPIs critical for coronavirus attachment/entry and serves as a first guide in the search for SMI-based alternative antiviral therapies for the prevention and treatment of diseases caused by coronaviruses in general and COVID-19 in particular.
Keywords	covid19
Language	English
Publishing date	2020-10-22
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.10.22.351056
Database	COVID19

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Article ; Online: Methylene Blue Inhibits In Vitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction – A Mechanism That Can Contribute to Its Antiviral Activity Against COVID-19

Bojadzic, Damir / Alcazar, Oscar / Buchwald, Peter

bioRxiv

Abstract	Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction with an activity similar, possibly slightly higher, than those found for it for other PPIs. This PPI inhibitory activity of methylene blue could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.
Keywords	covid19
Language	English
Publishing date	2020-08-31
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.08.29.273441
Database	COVID19

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Article ; Online: Drug-Integrating Amphiphilic Nanomaterial Assemblies: 1. Spatiotemporal control of cyclosporine delivery and activity using nanomicelles and nanofibrils.

Velluto, Diana / Bojadzic, Damir / De Toni, Teresa / Buchwald, Peter / Tomei, Alice A

Journal of controlled release : official journal of the Controlled Release Society

2020 Volume 329, Page(s) 955–970

Abstract: Immunomodulatory therapies are limited by unavoidable side effects as well as poor solubility, stability, and pharmacokinetic properties. Nanomaterial-based drug delivery may overcome these limitations by increasing drug solubility, site-targeting, and ... ...

Abstract	Immunomodulatory therapies are limited by unavoidable side effects as well as poor solubility, stability, and pharmacokinetic properties. Nanomaterial-based drug delivery may overcome these limitations by increasing drug solubility, site-targeting, and duration of action. Here, we prepared innovative drug-integrating amphiphilic nanomaterial assemblies (DIANA) with tunable hydrophobicity, size, and morphology, and we evaluated their ability to deliver cyclosporine A (CsA) for immunomodulatory applications. We synthesized amphiphilic block copolymers made of poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) and poly(ethylene glycol)-oligo(ethylene sulfide) (PEG-OES) that can self-assemble into solid core nanomicelles (nMIC, with ≈20 nm diameter) and nanofibrils (nFIB, with ≈5 nm diameter and > 500 nm length), respectively. nMIC and nFIB displayed good CsA encapsulation efficiency (up to 4.5 and 2 mg/mL, respectively in aqueous solution), superior to many other solubilization methods, and provided sustained release (>14 and > 7 days for the nMIC and nFIB) without compromising CsA's pharmacological activity. Treatment of insulin-secreting cells with unloaded DIANAs did not impair cell viability and functionality. Both CsA-loaded DIANAs inhibited the proliferation and activation of insulin-reactive cytotoxic T cells in vitro. Subcutaneous injections of CsA-loaded DIANAs in mice provided CsA sustained release, decreasing alloantigen-induced immune responses in the draining lymph node at lower doses and reduced administration frequency than unformulated CsA. While nMIC solubilized higher amounts and provided more sustained release of CsA in vitro, nFIB enhanced cellular uptake and promoted local retention due to slower trafficking in vivo. DIANAs provide a versatile platform for a local immune suppression regimen that can be applied to allogeneic cell transplantation.
MeSH term(s)	Animals ; Cyclosporine ; Drug Carriers ; Mice ; Micelles ; Nanostructures ; Polyethylene Glycols ; Solubility
Chemical Substances	Drug Carriers ; Micelles ; Polyethylene Glycols (3WJQ0SDW1A) ; Cyclosporine (83HN0GTJ6D)
Language	English
Publishing date	2020-10-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2020.10.026
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