A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands

Das, Samir; Nag, Arundhati; Liang, JingXin; Bunck, David N.; Umeda, Aiko; Farrow, Blake; Coppock, Matthew B.; Sarkes, Deborah A.; Finch, Amethist S.; Agnew, Heather D.; Pitram, Suresh M.; Lai, Bert; Yu, Mary Beth; Museth, Anna Katrine; Deyle, Kaycie M.; Lepe, Bianca; Rodriguez‐Rivera, Frances P.; McCarthy, Amy; Alvarez‐Villalonga, Belen; Chen, Ann; Heath, John E.; Stratis‐Cullum, Dimitra N.; Heath, James R.

doi:10.1002/anie.201505243

Cited by 47 publications

(87 citation statements)

References 38 publications

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“…18 We used our previously reported approach of epitope targeting combined with in situ click chemistry screening to develop three macrocyclic peptide ligands against relatively conserved motifs within the protein ( Figure 1C, D). 18 Polypeptides representing the targeted epitopes were synthesized, affixed with a click handle, and screened against combinatorial macrocyclic peptide libraries presenting the complementary click handle. This screen selects for ligands that bind to the synthetic HRP2 epitopes in just the right orientation to promote the (noncatalyzed) copper-free click reaction.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of heme sequestration of histidine‐rich protein 2 using multiple epitope‐targeted peptides

Liang

Bunck

Mishra

et al. 2019

Journal of Peptide Science

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Plasmodium falciparum is the most lethal species of malaria. In infected human red blood cells, P. falciparum digests hemoglobin as a nutrient source, liberating cytotoxic free heme in the process. Sequestration and subsequent conversion of this byproduct into hemozoin, an inert biocrystalline heme aggregate, plays a key role in parasite survival. Hemozoin has been a longstanding target of antimalarials such as chloroquine (CQ), which inhibit the biocrystallization of free heme. In this study, we explore heme‐binding interactions with histidine‐rich‐protein 2 (HRP2), a known malarial biomarker and purported player in free heme sequestration. HRP2 is notoriously challenging to target due to its highly repetitious sequence and irregular secondary structure. We started with three protein‐catalyzed capture agents (PCCs) developed against epitopes of HRP2, inclusive of heme‐binding motifs, and explored their ability to inhibit heme:HRP2 complex formation. Cocktails of the individual PCCs exhibit an inhibitory potency similar to CQ, while a covalently linked structure built from two separate PCCs provided considerably increased inhibition relative to CQ. Epitope‐targeted disruption of heme:HRP2 binding is a novel approach towards disrupting P. falciparum‐related hemozoin formation.

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Section: Introductionmentioning

confidence: 99%

Inhibition of heme sequestration of histidine‐rich protein 2 using multiple epitope‐targeted peptides

Liang

Bunck

Mishra

et al. 2019

Journal of Peptide Science

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“…(54,55) Epitope-targeted ligands against the MrkA protein AR-PCC ligands against the four selected epitopes were identified from a combinatorial library of macrocyclic peptides by using the epitope-targeted PCC method. (36)(37)(38)(39) This method exploits noncatalyzed click chemistry via an in situ click screen. For the screen, an alkyne-presenting, one-bead one-compound (OBOC) combinatorial library of approximately 1M peptide macrocycles with a 5residue variable region is screened against synthetic variants of the epitopes (SynEps).…”

Section: Figure 2 (A)mentioning

confidence: 99%

“…The second is an immunogenic antibody-recruiting (AR) label on the PCC that promotes pathogen phagocytosis by innate immune cells (Figure 1). To generate the AR-PCC ligand, we employed the recently reviewed, (35) all synthetic epitope-targeted protein-catalyzed capture agent (PCC) method, (36)(37)(38)(39) coupled with a bioinformatics approach to identify epitopes for targeting. By targeting highly exposed, antigenic epitopes of the Type 3 Fimbrial Shaft (MrkA) surface protein of K. pneumoniae, we developed a small macrocyclic peptide binder in a single generation screen.…”

Section: Introductionmentioning

confidence: 99%

Antibody-Recruiting Protein-Catalyzed Capture Agents to Combat Antibiotic-Resistant Bacteria

Idso

Akhade

Arrieta-Ortiz

et al. 2019

Preprint

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Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting proteincatalyzed capture agents (AR-PCCs), to address this challenge. We applied the combinatorial PCC technology to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic gram-negative pathogen with drug resistant strains. Multi-omic data combined with bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing ligand exhibited high-affinity (EC50~50 nM) to full-length MrkA, and selectively bound to MrkAexpressing K. pneumoniae, but not to other pathogenic bacterial species. AR-PCCs conjugated with immunogens promoted antibody recruitment to K. pneumoniae, leading to phagocytosis and phagocytic killing by macrophages. The rapid development of this highly targeted antibiotic implies that the integrated computational and synthetic toolkit described here can be used for the accelerated production of antibiotics against drug resistant bacteria. resistant K. pneumoniae, and that the basic technology might provide a route towards drugging "undruggable" pathogenic bacteria. Results and DiscussionMulti-omic analyses to select target a protein on K. pneumoniae Here we describe the algorithm used to identify protein targets, and epitopes on those targets, for drugging K. pneumoniae using AR-PCCs. Traditional drugging strategies tend to rely on disrupting the function of, for example, an enzyme by competing for occupancy within a strategic hydrophobic binding pocket. Our requirements are very different. Instead, favorable aspects of target proteins are high expression levels on only the pathogen of interest, plus localization of that protein to the outer membrane or extracellular space of the pathogen. Further, once such a target protein is identified, there are additional considerations regarding which epitopes of that protein present the greatest opportunities for exploiting AR-PCCs. The flow diagram in Figure 2A delineates the strategy for identifying MrkA as an ideal target protein. Protein expression levels can vary across environments and growth phases, so we analyzed the transcriptional data reported by Guilhen et al(40) to identify proteins

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“…[119] Die systematische N-Methylierung ausgewählter cyclischer Peptide hat das Potenzial, neue permeable Peptidmodalitäten zu ergeben. [125] Mit den neuartigen Peptiden lässt sich ein breiter und teils noch unerforschter chemischer Raum ausloten, was die Voraussetzung fürd ie Entwicklung synthetischer Liganden sein kçnnte,d ie Proteinstrukturen adressieren, denen definierte Bindungstaschen fehlen. [122] In einigen Fällen war das Klammern allein nicht ausreichend, um eine robuste Zellaufnahme zu gewährleisten, sodass im Anschluss an das Klammern eine Optimierung durchgeführt werden musste.…”

Section: Zusammenfassung Und Ausblick Zu Peptiden Und Peptidmimetikaunclassified

“…[95] Unabhängig davon versteht man die Bindung zwischen komplexeren Peptidgerüststrukturen und Proteinen besser, [124] wodurch Schleifenmimetika sowie verschiedene Cyclisierungsstrategien ermçglicht werden. [125] Mit den neuartigen Peptiden lässt sich ein breiter und teils noch unerforschter chemischer Raum ausloten, was die Voraussetzung fürd ie Entwicklung synthetischer Liganden sein kçnnte,d ie Proteinstrukturen adressieren, denen definierte Bindungstaschen fehlen.…”

Section: Peptidfoldamereunclassified

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

et al. 2017

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Unsere sich stetig erweiternden Kenntnisse über biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation möglicherweise neuartige Therapiemöglichkeiten für viele Krankheiten erschließt. Diese Angriffspunkte umfassen insbesondere Protein‐Protein‐ und Protein‐Nukleinsäure‐Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitäten werden daher benötigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitäten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgerüststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berücksichtigt. Wir stellen die repräsentativsten Beispiele dieser Modalitäten vor, die auf große Bindungsoberflächen, wie sie in Protein‐Protein‐Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgänge abzielen.

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A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands

Cited by 47 publications

References 38 publications

Inhibition of heme sequestration of histidine‐rich protein 2 using multiple epitope‐targeted peptides

Inhibition of heme sequestration of histidine‐rich protein 2 using multiple epitope‐targeted peptides

Antibody-Recruiting Protein-Catalyzed Capture Agents to Combat Antibiotic-Resistant Bacteria

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

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