bims-cepepe 2024-05-12 papers

Issue of 2024‒05‒12
five papers selected by
Henry Lamb, Queensland University of Technology

Brief Bioinform. 2024 Mar 27. pii: bbae215. [Epub ahead of print]25(3):

HighFold: accurately predicting structures of cyclic peptides and complexes with head-to-tail and disulfide bridge constraints.

Chenhao Zhang, Chengyun Zhang, Tianfeng Shang, Ning Zhu, Xinyi Wu, Hongliang Duan.

In recent years, cyclic peptides have emerged as a promising therapeutic modality due to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes is crucial for unlocking invaluable insights about protein target-cyclic peptide interaction, which can facilitate the development of novel-related drugs. However, conducting experimental observations is time-consuming and expensive. Computer-aided drug design methods are not practical enough in real-world applications. To tackles this challenge, we introduce HighFold, an AlphaFold-derived model in this study. By integrating specific details about the head-to-tail circle and disulfide bridge structures, the HighFold model can accurately predict the structures of cyclic peptides and their complexes. Our model demonstrates superior predictive performance compared to other existing approaches, representing a significant advancement in structure-activity research. The HighFold model is openly accessible at https://github.com/hongliangduan/HighFold.

Keywords: cyclic peptides; deep learning; structure prediction

DOI: https://doi.org/10.1093/bib/bbae215

Trends Pharmacol Sci. 2024 May 08. pii: S0165-6147(24)00069-5. [Epub ahead of print]

Peptide libraries: from epitope mapping to in-depth high-throughput analysis.

Debora Iaculli, Steven Ballet.

Peptide arrays are a valuable instrument in the characterization of protein-protein interactions (PPIs) and immunogenic regions. New methods were developed to exploit the high-throughput potential of peptide arrays to obtain more in-depth information, replacing traditional resource-intensive experiments. Here, we discuss the recent advances in peptide-array-based technologies and the remaining challenges.

Keywords: epitope mapping; peptide arrays; peptide libraries; peptide scanning; protein–protein interactions

DOI: https://doi.org/10.1016/j.tips.2024.04.004

J Drugs Dermatol. 2024 May 01. 23(5): 347-352

So Let's Design a Peptide . . . A Physician's Approach.

Alan D Widgerow.

This paper outlines a process undertaken by a physician to design a peptide aimed at impacting the extracellular matrix. From a position of very little expertise, a new peptide was designed with amino acid constituents based on the structural proteins collagen and elastin. Sequencing was also considered, given the periodic repetition observed in these proteins, and a peptide with reasonable molecular weight and physical characteristics was designed using available software. The sequence of events concerning intellectual property, functionality investigation, and eventual use of the peptide in new formulations is detailed. This may be of interest to physicians who consider this exercise out of the scope of the usual practice. J Drugs Dermatol. 2024;23(5):347-352.    doi:10.36849/JDD.7921.

DOI: https://doi.org/10.36849/JDD.7921

Cancer Discov. 2024 May 08.

D3S-001, a KRAS G12C inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities.

Jing Zhang, Sun Min Lim, Mi Ra Yu, Cheng Chen, Jia Wang, Wenqian Wang, Haopeng Rui, Jingtao Lu, Shun Lu, Tony Mok, Zhi Jian Chen, Byoung C Cho.

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its GDP- and GTP-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a next generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as EGF and HGF, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust anti-tumor activity preclinically and translated into promising clinical activity in an ongoing phase 1 trial (NCT05410145).

DOI: https://doi.org/10.1158/2159-8290.CD-24-0006

Nucl Med Commun. 2024 May 10.

A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer.

Richard F Liu, Cristiano Ferrario, Parvaneh Fallah, April A N Rose, Soumaya Labidi, Aline Mamo, Stephan M Probst.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment.METHODS: We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed.
RESULTS: Eleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia.
CONCLUSION: 131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.

DOI: https://doi.org/10.1097/MNM.0000000000001858