Computational discovery of tripeptide inhibitors targeting monkeypox virus A42R profilin-like protein.

Monkeypox is an infectious disease caused by the monkeypox virus (MPXV), a member of the Orthopoxvirus genus closely related to smallpox. The structure of the A42R profilin-like protein is the first and only available structure among MPXV proteins. Biochemical studies of A42R were conducted in the 1990s and later work also analyzed the protein's function in viral replication in cells. This study aims to screen tripeptides for their potential inhibition of the A42R profilin-like protein using computational methods, with implications for MPXV therapy. A total of 8000 tripeptides underwent molecular docking simulations, resulting in the identification of 20 compounds exhibiting strong binding affinity to A42R. To validate the docking results, molecular dynamics simulations and free energy perturbation calculations were performed. These analyses revealed two tripeptides with sequences TRP-THR-TRP and TRP-TRP-TRP, which displayed robust binding affinity to A42R. Markedly, electrostatic interactions predominated over van der Waals interactions in the binding process between tripeptides and A42R. Three A42R residues, namely Glu9, Ser12, and Arg38, appear to be pivotal in mediating the interaction between A42R and the tripeptide ligands. Notably, tripeptides containing two or three tryptophan residues demonstrate a pronounced binding affinity, with the tripeptide comprising three tryptophan amino acids showing the highest level of affinity. These findings offer valuable insights for the selection of compounds sharing a similar structure and possessing a high affinity for A42R, potentially capable of inhibiting its enzyme activity. The study highlights a structural advantage and paves the way for the development of targeted therapies against MPXV infections.

Autoimmune Limbic Encephalitis in Patients with Hematologic Malignancies after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with post-transplant cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflammatory biomarkers, and reconstitution of various T cell populations. Of 35 patients, 4 developed LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.

Carbaborane-substituted 1,2,3-triphospholanes and 1-aza-2,5-diphospholane: new synthetic approaches.

New phosphorus-containing, five-membered P,P,P and P,N,P heterocycles were synthesized and fully characterized. The P,P,P heterocycles, 1,2,3-triphospholanes, can be synthesized by two different facile pathways, whereas the P,N,P compound, a 1-aza-2,5-diphospholane, can only be obtained with silylamine.