bims-cepepe 2024-04-07 papers

RSC Chem Biol. 2024 Apr 03. 5(4): 328-334

Cell penetration of oxadiazole-containing macrocycles.

Sungjoon Huh, Nefeli Batistatou, Jing Wang, George J Saunders, Joshua A Kritzer, Andrei K Yudin.

Passive membrane permeability is an important property in drug discovery and biological probe design. To elucidate the cell-penetrating ability of oxadiazole-containing (Odz) peptides, we employed the Chloroalkane Penetration Assay. The present study demonstrates that Odz cyclic peptides can be highly cell-penetrant depending on the position of specific side chains and the chloroalkane tag. Solution NMR shows that Odz cyclic peptides adopt a β-turn conformation. However, despite observing high cell penetration, we observed low passive permeability in experiments with artificial membranes. These findings highlight the complexity of controlling cell penetration for conformationally sensitive macrocycles and suggest that Odz cyclic peptides may provide a framework for designing cell-penetrant cyclic peptides.

DOI: https://doi.org/10.1039/d3cb00201b

Biochimie. 2024 Mar 30. pii: S0300-9084(24)00070-1. [Epub ahead of print]

Multifunctional host-defense peptides isolated from skin secretions of the banana tree dwelling frog Boana platanera (Hylidae; Hylinae).

J Michael Conlon, Ananyaa Sridhar, Dawood Khan, Taylor S Cunning, Jack J Delaney, Megan G Taggart, Nigel G Ternan, Jérôme Leprince, Laurent Coquet, Thierry Jouenne, Samir Attoub, Milena Mechkarska.

Five host-defense peptides (figainin 2PL, hylin PL, raniseptin PL, plasticin PL, and peptide YL) were isolated from norepinephrine-stimulated skin secretions of the banana tree dwelling frog Boana platanera (Hylidae; Hylinae) collected in Trinidad. Raniseptin PL (GVFDTVKKIGKAVGKFALGVAKNYLNS.NH2) and figainin 2PL (FLGTVLKLGKAIAKTVVPMLTNAMQP KQ.NH2) showed potent and rapid bactericidal activity against a range of clinically relevant Gram-positive and Gram-negative ESKAPE + pathogens and Clostridioides difficile. The peptides also showed potent cytotoxic activity (LC50 values < 30 μM) against A549, MDA-MB-231 and HT29 human tumor-derived cell lines but appreciably lower hemolytic activity against mouse erythrocytes (LC50 = 262 ± 14 μM for raniseptin PL and 157 ± 16 μM for figainin 2PL). Hylin PL (FLGLIPALAGAIGNLIK.NH2) showed relatively weak activity against microorganisms but was more hemolytic. The glycine-leucine-rich peptide with structural similarity to the plasticins (GLLSTVGGLVGGLL NNLGL.NH2) and the non-cytotoxic peptide YL (YVPGVIESLL.NH2) lacked antimicrobial and cytotoxic activities. Hylin PL, raniseptin-PL and peptide YL stimulated the rate of release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥100 nM. Peptide YL was the most effective (2.3-fold increase compared with basal rate at 1 μM concentration) and may represent a template for the design of a new class of incretin-based anti-diabetic drugs.

Keywords: Amphibia; Anti-cancer; Anti-diabetic; Antimicrobial; Cytotoxicity; Insulinotropic; Type 2 diabetes

DOI: https://doi.org/10.1016/j.biochi.2024.03.012

Science. 2024 Apr 05. 384(6691): 106-112

De novo design of drug-binding proteins with predictable binding energy and specificity.

Lei Lu, Xuxu Gou, Sophia K Tan, Samuel I Mann, Hyunjun Yang, Xiaofang Zhong, Dimitrios Gazgalis, Jesús Valdiviezo, Hyunil Jo, Yibing Wu, Morgan E Diolaiti, Alan Ashworth, Nicholas F Polizzi, William F DeGrado.

The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free energy calculations performed directly on the designed models were in excellent agreement with the experimentally measured affinities. We conclude that de novo design of high-affinity small molecule-binding proteins with tuned interaction energies is feasible entirely from computation.

DOI: https://doi.org/10.1126/science.adl5364

Int Immunopharmacol. 2024 Apr 03. pii: S1567-5769(24)00452-1. [Epub ahead of print]132 111934

Regulatory T cells as crucial trigger and potential target for hyperprogressive disease subsequent to PD-1/PD-L1 blockade for cancer treatment.

Zhe Ren, Kaiqing Yang, Lin Zhu, Detao Yin, Yubing Zhou.

PD-1/PD-L1 blockade therapy has brought great success to cancer treatment. Nevertheless, limited beneficiary populations and even hyperprogressive disease (HPD) greatly constrain the application of PD-1/PD-L1 inhibitors in clinical treatment. HPD is a special pattern of disease progression with rapid tumor growth and even serious consequences of patient death, which requires urgent attention. Among the many predisposing causes of HPD, regulatory T cells (Tregs) are suspected because they are amplified in cases of HPD. Tregs express PD-1 thus PD-1/PD-L1 blockade therapy may have an impact on Tregs which leads to HPD. Tregs are a subset of CD4+ T cells expressing FoxP3 and play critical roles in suppressing immunity. Tregs migrate toward tumors in the presence of chemokines to suppress antitumor immune responses, causing cancer cells to grow and proliferate. Studies have shown that deleting Tregs could enhance the efficacy of PD-1/PD-L1 blockade therapy and reduce the occurrence of HPD. This suggests that immunotherapy combined with Treg depletion may be an effective means of avoiding HPD. In this review, we summarized the immunosuppressive-related functions of Tregs in antitumor therapy and focused on advances in therapy combining Tregs depletion with PD-1/PD-L1 blockade in clinical studies. Moreover, we provided an outlook on Treg-targeted HPD early warning for PD-1/PD-L1 blockade therapy.

Keywords: Cancer; Hyperprogressive disease; Immune checkpoint; PD-1/PD-L1 blockade; Regulatory T cells

DOI: https://doi.org/10.1016/j.intimp.2024.111934

Nat Commun. 2024 Apr 02. 15(1): 2831

An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction.

Xinyu He, Jie Li, Xinxin Liang, Wuyu Mao, Xinglong Deng, Meng Qin, Hao Su, Haoxing Wu.

The prodrug design strategy offers a potent solution for improving therapeutic index and expanding drug targets. However, current prodrug activation designs are mainly responsive to endogenous stimuli, resulting in unintended drug release and systemic toxicity. In this study, we introduce 3-vinyl-6-oxymethyl-tetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling peptides to produce bioorthogonal activable peptide-prodrug conjugates. These stable prodrugs can selectively bind to target cells, facilitating cellular uptake. Subsequent bioorthogonal cleavage reactions trigger prodrug activation, significantly boosting potency against tumor cells while maintaining exceptional off-target safety for normal cells. In vivo studies demonstrate the therapeutic efficacy and safety of this prodrug design approach. Given the broad applicability of functional groups and labeling versatility with voTz, we foresee that this strategy will offer a versatile solution to enhance the therapeutic range of cytotoxic agents and facilitate the development of bioorthogonal activatable biopharmaceuticals and biomaterials.

DOI: https://doi.org/10.1038/s41467-024-47188-6

Nat Commun. 2024 Apr 03. 15(1): 2875

ReLo is a simple and rapid colocalization assay to identify and characterize direct protein-protein interactions.

Harpreet Kaur Salgania, Jutta Metz, Mandy Jeske.

The characterization of protein-protein interactions (PPIs) is fundamental to the understanding of biochemical processes. Many methods have been established to identify and study direct PPIs; however, screening and investigating PPIs involving large or poorly soluble proteins remains challenging. Here, we introduce ReLo, a simple, rapid, and versatile cell culture-based method for detecting and investigating interactions in a cellular context. Our experiments demonstrate that ReLo specifically detects direct binary PPIs. Furthermore, we show that ReLo bridging experiments can also be used to determine the binding topology of subunits within multiprotein complexes. In addition, ReLo facilitates the identification of protein domains that mediate complex formation, allows screening for interfering point mutations, and it is sensitive to drugs that mediate or disrupt an interaction. In summary, ReLo is a simple and rapid alternative for the study of PPIs, especially when studying structurally complex proteins or when established methods fail.

DOI: https://doi.org/10.1038/s41467-024-47233-4

J Cancer. 2024 ;15(9): 2538-2548

PHGDH is Key to a Prognostic Multigene Signature and a Potential Therapeutic Target in Acute Myeloid Leukemia.

Jiagui Zhong, Kezhi Huang, Shaofan Xie, Ailian Tan, Jiaqin Peng, Danian Nie, Liping Ma, Yiqing Li.

As a rate-limiting enzyme for the serine biosynthesis pathway (SSP) in the initial step, phosphoglycerate dehydrogenase (PHGDH) is overexpressed in many different tumors, and pharmacological or genetic inhibition of PHGDH promotes antitumor effects. In the present research, by analyzing several acute myeloid leukemia (AML) datasets in the Gene Expression Omnibus (GEO), we identified prognosis-related genes and constructed a multigene signature by univariate, multivariate Cox regression and LASSO regression. Subsequently, the multigene signature was confirmed through Cox, Kaplan-Meier, and ROC analyses in the validation cohort. Moreover, PHGDH acted as a risk factor and was correlated with inferior overall survival. We further analysed other datasets and found that PHGDH was overexpressed in AML. Importantly, the expression of PHGDH was higher in drug-resistant AML compared to drug-sensitive ones. In vitro experiments showed that inhibition of PHGDH induced apoptosis and reduced proliferation in AML cells, and these antitumor effects could be related to the Bcl-2/Bax signaling pathway by the noncanonical or nonmetabolic functions of PHGDH. In summary, we constructed a twenty-gene signature that could predicate prognosis of AML patients and found that PHGDH may be a potential target for AML treatment.

Keywords: Acute myeloid leukemia; Gene signature; Overall survival; PHGDH; Therapeutic target

DOI: https://doi.org/10.7150/jca.90822

Prostate. 2024 Apr 01.

Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting.
METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders.
RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group.
CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

Keywords: androgen deprivation therapy intensification; metastatic prostate cancer; survival outcomes

DOI: https://doi.org/10.1002/pros.24696