Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid-Free Analgesics.

The opioid crisis has highlighted the urgent need to develop non-opioid alternatives for managing pain, with an effective, safe, and non-addictive pharmacotherapeutic profile. Using an extensive structure-activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid-independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile residue of NT(7-12) was substituted by cyclopentylalanine, Pro and Pro were replaced by allyl-glycine followed by side-chain to side-chain cyclization is the most selective analog targeting NTS2 identified to date (K 2.

Rational Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket.

TMPRSS6 is a potential therapeutic target for the treatment of iron overload due to its role in regulating levels of hepcidin. Although potent TMPRSS6 inhibitors have been previously developed, their lack of specificity requires optimization to avoid potential side effects before pursuing preclinical development with models. Here, using computer-aided drug design based on a TMPRSS6 homology model, we reveal that the S2 position of TMPRSS6 offers a potential avenue to achieve selectivity against other members of the TTSP family.

Comparative Analysis of Cyclization Techniques in Stapled Peptides: Structural Insights into Protein-Protein Interactions in a SARS-CoV-2 Spike RBD/hACE2 Model System.

Medicinal chemistry is constantly searching for new approaches to develop more effective and targeted therapeutic molecules. The design of peptidomimetics is a promising emerging strategy that is aimed at developing peptides that mimic or modulate the biological activity of proteins. Among these, stapled peptides stand out for their unique ability to stabilize highly frequent helical motifs, but they have failed to be systematically reported.

Secondary glaucoma in small versus large uveal melanoma patients treated with stereotactic radiosurgery on linear accelerator.

Aim: Secondary radiation-related side effects like secondary glaucoma (SG) of different modalities of treatment in uveal melanoma patients can appear in certain interval after therapy. This study describes the incidence of SG in patients after stereotactic radiosurgery (SRS).

Method: The data of 230 patients treated by SRS were reviewed for SG.

Long-term outcomes of prostaglandin analog versus timolol maleate in ocular hypertensive or primary open-angle glaucoma patients in Europe.

Purpose: To determine the direct costs of therapy over 5 years of a European monotherapy cohort begun on a prostaglandin (PTG) versus timolol in patients with primary open-angle glaucoma or ocular hypertension.

Methods: A retrospective, multicenter, active-controlled, observational study. Data were abstracted for European patients treated as initial monotherapy in 1996 or afterward, with 5 years of available records.