Alpha-1 antitrypsin inhibits pertussis toxin.

Pertussis (whooping cough) is a vaccine-preventable but re-emerging, highly infectious respiratory disease caused by Bordetella pertussis. There are currently no effective treatments for pertussis, complicating care for nonvaccinated individuals, especially newborns. Disease manifestations are predominantly caused by pertussis toxin (PT), a pivotal virulence factor classified as an ADP-ribosylating AB-type protein toxin.

Rational design based on multi-monomer simultaneous docking for epitope imprinting of SARS-CoV-2 spike protein.

Among biomimetic strategies shaping engineering designs, molecularly imprinted polymer (MIP) technology stands out, involving chemically synthesised receptors emulating natural antigen-antibody interactions. These versatile 'designer polymers' with remarkable stability and low cost, are pivotal for in vitro diagnostics. Amid the recent global health crisis, we probed MIPs' potential to capture SARS-CoV-2 virions.

Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity.

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication. Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis.

A naturally occurring 22-amino acid fragment of human hemoglobin A inhibits autophagy and HIV-1.

Autophagy is an evolutionarily ancient catabolic pathway and has recently emerged as an integral part of the innate immune system. While the core machinery of autophagy is well defined, the physiological regulation of autophagy is less understood. Here, we identify a C-terminal fragment of human hemoglobin A (HBA1, amino acids 111-132) in human bone marrow as a fast-acting non-inflammatory inhibitor of autophagy initiation.

An Optimized Peptide Antagonist of CXCR4 Limits Survival of BCR-ABL1-Transformed Cells in Philadelphia-Chromosome-Positive B-Cell Acute Lymphoblastic Leukemia.

Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR-ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR-ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR-ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4.

Fatty acid conjugated EPI-X4 derivatives with increased activity and in vivo stability.

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity.

Semen enhances transmitted/founder HIV-1 infection and only marginally reduces antiviral activity of broadly neutralizing antibodies.

Topically applied microbicides may play a critical role in preventing sexual transmission of human immunodeficiency virus type 1 (HIV-1); however, their efficacy can be compromised by amyloid fibrils present in semen, which significantly increase HIV-1 infectivity. This phenomenon may have contributed to the failure of most microbicide candidates in clinical settings. Understanding the impact of semen on microbicide effectiveness is thus crucial.

Isolation and Characterization of Neutralizing Monoclonal Antibodies from a Large Panel of Murine Antibodies against RBD of the SARS-CoV-2 Spike Protein.

The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new variants, continues to underscore the importance of remaining vigilant and adaptable. Monoclonal antibodies (mAbs) have stood out as a powerful and immediate therapeutic response to COVID-19.

Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2.

Long COVID (LC) occurs after at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, yet its etiology remains poorly understood. We used 'omic" assays and serology to deeply characterize the global and SARS-CoV-2-specific immunity in the blood of individuals with clear LC and non-LC clinical trajectories, 8 months postinfection. We found that LC individuals exhibited systemic inflammation and immune dysregulation.

Optimized peptide nanofibrils as efficient transduction enhancers for and gene transfer.

Chimeric antigen receptor (CAR)-T cell therapy is a groundbreaking immunotherapy for cancer. However, the intricate and costly manufacturing process remains a hurdle. Improving the transduction rate is a potential avenue to cut down costs and boost therapeutic efficiency.

Conformational States of the CXCR4 Inhibitor Peptide EPI-X4-A Theoretical Analysis.

EPI-X4, an endogenous peptide inhibitor, has exhibited potential as a blocker of CXCR4-a G protein-coupled receptor. This unique inhibitor demonstrates the ability to impede HIV-1 infection and halt CXCR4-dependent processes such as tumor cell migration and invagination. Despite its promising effects, a comprehensive understanding of the interaction between EPI-X4 and CXCR4 under natural conditions remains elusive due to experimental limitations.

Peptide Amphiphiles as Biodegradable Adjuvants for Efficient Retroviral Gene Delivery.

Retroviral gene delivery is the key technique for in vitro and ex vivo gene therapy. However, inefficient virion-cell attachment resulting in low gene transduction efficacy remains a major challenge in clinical applications. Adjuvants for ex vivo therapy settings need to increase transduction efficiency while being easily removed or degraded post-transduction to prevent the risk of venous embolism after infusing the transduced cells back to the bloodstream of patients, yet no such peptide system have been reported thus far.

Development of N-Terminally Modified Variants of the CXCR4-Antagonistic Peptide EPI-X4 for Enhanced Plasma Stability.

EPI-X4, a natural peptide CXCR4 antagonist, shows potential for treating inflammation and cancer, but its short plasma stability limits its clinical application. We aimed to improve the plasma stability of EPI-X4 analogues without compromising CXCR4 antagonism. Our findings revealed that only the peptide N-terminus is prone to degradation.

Heterologous DNA-prime/protein-boost immunization with a monomeric SARS-CoV-2 spike antigen redundantizes the trimeric receptor-binding domain structure to induce neutralizing antibodies in old mice.

A multitude of alterations in the old immune system impair its functional integrity. Closely related, older individuals show, for example, a reduced responsiveness to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. However, systematic strategies to specifically improve the efficacy of vaccines in the old are missing or limited to simple approaches like increasing the antigen concentration or injection frequencies.

Peptide Bispecifics Inhibiting HIV-1 Infection by an Orthogonal Chemical and Supramolecular Strategy.

Viral infections pose a significant threat to human health, and effective antiviral strategies are urgently needed. Antiviral peptides have emerged as a promising class of therapeutic agents due to their unique properties and mechanisms of action. While effective on their own, combining antiviral peptides may allow us to enhance their potency and to prevent viral resistance.

Data-mining unveils structure-property-activity correlation of viral infectivity enhancing self-assembling peptides.

Gene therapy via retroviral vectors holds great promise for treating a variety of serious diseases. It requires the use of additives to boost infectivity. Amyloid-like peptide nanofibers (PNFs) were shown to efficiently enhance retroviral gene transfer.

Cryo-EM structure and polymorphic maturation of a viral transduction enhancing amyloid fibril.

Amyloid fibrils have emerged as innovative tools to enhance the transduction efficiency of retroviral vectors in gene therapy strategies. In this study, we used cryo-electron microscopy to analyze the structure of a biotechnologically engineered peptide fibril that enhances retroviral infectivity. Our findings show that the peptide undergoes a time-dependent morphological maturation into polymorphic amyloid fibril structures.

Spermine and spermidine bind CXCR4 and inhibit CXCR4- but not CCR5-tropic HIV-1 infection.

Semen is an important vector for sexual HIV-1 transmission. Although CXCR4-tropic (X4) HIV-1 may be present in semen, almost exclusively CCR5-tropic (R5) HIV-1 causes systemic infection after sexual intercourse. To identify factors that may limit sexual X4-HIV-1 transmission, we generated a seminal fluid-derived compound library and screened it for antiviral agents.

ACE2-EGFR-MAPK signaling contributes to SARS-CoV-2 infection.

SARS-CoV-2 triggered the most severe pandemic of recent times. To enter into a host cell, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2). However, subsequent studies indicated that other cell membrane receptors may act as virus-binding partners.

Inverse design of viral infectivity-enhancing peptide fibrils from continuous protein-vector embeddings.

Amyloid-like nanofibers from self-assembling peptides can promote viral gene transfer for therapeutic applications. Traditionally, new sequences are discovered either from screening large libraries or by creating derivatives of known active peptides. However, the discovery of peptides, which are sequence-wise not related to any known active peptides, is limited by the difficulty to rationally predict structure-activity relationships because their activities typically have multi-scale and multi-parameter dependencies.

Post-acute immunological and behavioral sequelae in mice after Omicron infection.

Progress in understanding long COVID and developing effective therapeutics is hampered in part by the lack of suitable animal models. Here we used ACE2-transgenic mice recovered from Omicron (BA.1) infection to test for pulmonary and behavioral post-acute sequelae.

Development of a New Class of CXCR4-Targeting Radioligands Based on the Endogenous Antagonist EPI-X4 for Oncological Applications.

The peptide fragment of human serum albumin that was identified as an inhibitor of C-X-C motif chemokine receptor 4 (CXCR4), termed EPI-X4, was investigated as a scaffold for the development of CXCR4-targeting radio-theragnostics. Derivatives of its truncated version JM#21 (ILRWSRKLPCVS) were conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and tested in Jurkat and Ghost-CXCR4 cells. Ligand-, -, -, -, -, -, and - were selected for radiolabeling.

The C-terminal 32-mer fragment of hemoglobin alpha is an amyloidogenic peptide with antimicrobial properties.

Antimicrobial peptides (AMPs) are major components of the innate immune defense. Accumulating evidence suggests that the antibacterial activity of many AMPs is dependent on the formation of amyloid-like fibrils. To identify novel fibril forming AMPs, we generated a spleen-derived peptide library and screened it for the presence of amyloidogenic peptides.