bims-polyam 2023-06-04 papers

Issue of 2023–06–04
six papers selected by
Sebastian J. Hofer, University of Graz

Neurosurgery. 2023 May 29.

Glioma Metabolic Feedback In Situ: A First-In-Human Pharmacodynamic Trial of Difluoromethylornithine + AMXT-1501 Through High-Molecular Weight Microdialysis.

Cecile Riviere-Cazaux, Bryan J Neth, Matthew D Hoplin, Bambi Wessel, Jason Miska, Sani H Kizilbash, Terry C Burns.

BACKGROUND AND OBJECTIVES: No new drug has improved survival for glioblastoma since temozolomide in 2005, due in part to the relative inaccessibility of each patient's individualized tumor biology and its response to therapy. We have identified a conserved extracellular metabolic signature of enhancing high-grade gliomas enriched for guanidinoacetate (GAA). GAA is coproduced with ornithine, the precursor to protumorigenic polyamines through ornithine decarboxylase (ODC). AMXT-1501 is a polyamine transporter inhibitor that can overcome tumoral resistance to the ODC inhibitor, difluoromethylornithine (DFMO). We will use DFMO with or without AMXT-1501 to identify candidate pharmacodynamic biomarkers of polyamine depletion in patients with high-grade gliomas in situ. We aim to determine (1) how blocking polyamine production affects intratumoral extracellular guanidinoacetate abundance and (2) the impact of polyamine depletion on the global extracellular metabolome within live human gliomas in situ.
METHODS: DFMO, with or without AMXT-1501, will be administered postoperatively in 15 patients after clinically indicated subtotal resection for high-grade glioma. High-molecular weight microdialysis catheters implanted into residual tumor and adjacent brain will be used for postoperative monitoring of extracellular GAA and polyamines throughout therapeutic intervention from postoperative day (POD) 1 to POD5. Catheters will be removed on POD5 before discharge.
EXPECTED OUTCOMES: We anticipate that GAA will be elevated in tumor relative to adjacent brain although it will decrease within 24 hours of ODC inhibition with DFMO. If AMXT-1501 effectively increases the cytotoxic impact of ODC inhibition, we expect an increase in biomarkers of cytotoxicity including glutamate with DFMO + AMXT-1501 treatment when compared with DFMO alone.
DISCUSSION: Limited mechanistic feedback from individual patients' gliomas hampers clinical translation of novel therapies. This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.

DOI: https://doi.org/10.1227/neu.0000000000002511

Eur J Med Chem. 2023 May 08. pii: S0223-5234(23)00437-3. [Epub ahead of print]257 115471

Molecular-level strategic goals and repressors in Leishmaniasis - Integrated data to accelerate target-based heterocyclic scaffolds.

M Abirami, Banoth Karan Kumar, Faheem, Sanchita Dey, Samridhi Johri, Rosa M Reguera, Rafael Balaña-Fouce, Kondapalli Venkata Gowri Chandra Sekhar, Murugesan Sankaranarayanan.

Leishmaniasis is a complex of neglected tropical diseases caused by various species of leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, these drugs have many drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Among several identified potential molecular targets, enzymes involved in the purine salvage pathway include polyamine biosynthetic process, such as arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, trypanothione reductase as well as enzymes in the DNA cell cycle, such as DNA topoisomerases I and II plays vital role in the life cycle survival of leishmanial parasite. This review mainly focuses on various heterocyclic scaffolds, and their specific inhibitory targets against leishmaniasis, particularly those from the polyamine biosynthesis pathway and DNA topoisomerases with estimated activity studies of various heterocyclic analogs in terms of their IC50 or EC50 value, reported molecular docking analysis from available published literatures.

Keywords: Computational studies; Inhibitors; Leishmaniasis; Molecular targets

DOI: https://doi.org/10.1016/j.ejmech.2023.115471

Amino Acids. 2023 May 31.

The first evidence of biological activity for free Hypusine, an enigmatic amino acid discovered in the '70s.

Leticia Tamborlin, Karina Danielle Pereira, Dimitrius Santiago Passos Simões Fróes Guimarães, Leonardo Reis Silveira, Augusto Ducati Luchessi.

Hypusine amino acid [Nε-(4-amino-2-hydroxybutyl)-lysine] was first isolated in 1971 from bovine brain extracts. Hypusine originates from a post-translational modification at the eukaryotic translation initiation factor 5A (eIF5A), a protein produced by archaebacteria and eukaryotes. The eIF5A protein is the only one described containing the hypusine residue, which is essential for its activity. Hypusine as a free amino acid is a consequence of proteolytic degradation of eIF5A. Herein, we showed, for the first time, evidence of biological activity for the free hypusine. C6 rat glioma cells were treated with hypusine, and different cellular parameters were evaluated. Hypusine treatment significantly reduced C6 cell proliferation and potently suppressed their clonogenic capacity without leading to apoptosis. Hypusine also decreased the Eif5A transcript content and the global protein synthesis profile that may occur due to negative feedback in response to high hypusine concentration, controlling the content of newly synthesized eIF5A, which can affect the translation process. Besides, hypusine treatment also altered cellular metabolism by changing the pathways for energy production, reducing cellular respiration coupled with oxidative phosphorylation, and increasing the anaerobic metabolism. These observed results and the relationship between eIF5A and tumor processes led us to test the combination of hypusine with the chemotherapeutic drug temozolomide. Combining temozolomide with hypusine reduced the MTT conversion to the same levels as those observed using double temozolomide dosage alone, demonstrating a synergetic action between the compounds. Thus, since 1971, this is the first study showing evidence of biological activity for hypusine not associated with being an essential component of the eiF5A protein. Finding out the molecular targets of hypusine are the following efforts to completely characterize its biological activity.

Keywords: Cell proliferation; Hypusine; Oxidative metabolism; Post-translational modification; Protein synthesis; eIF5A

DOI: https://doi.org/10.1007/s00726-023-03283-4

Mol Cell. 2023 Jun 01. pii: S1097-2765(23)00368-4. [Epub ahead of print]83(11): 1765-1766

An unexpected pathway to polyamines in pancreatic cancer.

Dominik Awad, Costas A Lyssiotis.

In most adult tissues, arginine is the precursor to polyamines, poly-cationic metabolites that interact with negatively charged biomolecules like DNA. Lee et al.1 discovered that pancreatic cancers synthesize polyamines from glutamine, illuminating a new pathway and underscoring their metabolic flexibility.

DOI: https://doi.org/10.1016/j.molcel.2023.05.014

Infect Immun. 2023 Jun 01. e0016723

A Candidate Bacterial-Type Amino Acid Decarboxylase Is Essential for Male Gamete Exflagellation and Mosquito Transmission of the Malaria Parasite.

Umit Y Kina, Mohd Kamil, Gozde Deveci, Ab Matteen Rafiqi, Kai Matuschewski, Ahmed S I Aly.

A frequent side effect of chemotherapy against malaria parasite blood infections is a dramatic induction of the sexual blood stages, thereby enhancing the risk of future malaria transmissions. The polyamine biosynthesis pathway has been suggested as a candidate target for transmission-blocking anti-malarial drug development. Herein, we describe the role of a bacterial-type amino acid decarboxylase (AAD) in the life cycle of the malaria model parasite Plasmodium yoelii. Hallmarks of AAD include a conserved catalytic lysine residue and high-level homology to arginine/lysine/ornithine decarboxylases of pathogenic bacteria. By targeted gene deletion, we show that AAD plays an essential role in the exflagellation of microgametes, resulting in complete absence of sporozoites in the mosquito vector. These data highlight the central role of the biosysthesis of polyamines in the final steps of male gamete sexual development of the malaria parasite and, hence, onward transmission to mosquitoes.

Keywords: Malaria; Plasmodium; amino acid decarboxylase; blood stages; exflagellation; gametes; mosquito transmission; polyamine

DOI: https://doi.org/10.1128/iai.00167-23