Discovery of allosteric regulators with clinical potential to stabilize alpha-L-iduronidase in mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disease caused by lowered activity of the enzyme alpha-L-iduronidase (IDUA). Current therapeutic options show limited efficacy and do not treat some important aspects of the disease. Therefore, it may be advantageous to identify strategies that could improve the efficacy of existing treatments.

Anterolateral Thigh Free Flap Donor-Site Morbidity: A Retrospective Cohort Study.

The ability to achieve a good functional outcome, quality of life, and patient satisfaction related to the donor site of free flaps is an important factor in flap selection. One of the main advantages of an anterolateral thigh (ALT) free flap is its minimal donor-site morbidity. We conducted a study to analyze healing of ALT flap donor sites based on the type of closure.

Vram flap transposition in pelviperineal reconstruction. A technical note.

The vertical rectus abdominis myocutaneous flap is a workhorse flap for perineal reconstruction after pelvic exenteration with low rate of complications. When flap viability is compromised, it is principally due to an incorrect inset or inadequate postoperative care. The aim of this article is to specify the technical details that must be taken into account during VRAM flap transposition inside the pelvis.

Using Free Arterialized Venous Flaps for Reconstructing Hand Defects.

Hand and digit soft tissue defects are quite common and frequently require specialized reconstruction. When local flaps cannot be used to reconstruct a soft tissue defect, free flaps must be utilized. To overcome tissue volume and discrepancies in vessel diameter, arterialized venous free flaps from the forearm may provide an acceptable alternative.

Soft-Tissue Sarcoma as a Potential Differential Diagnosis of an Exophytic Soft-Tissue Mass: A Case Report.

The detection of a soft-tissue mass requires a detailed and conscientious examination to make a definitive diagnosis and propose appropriate treatment strategies. Benign mesenchymal tumors occur more frequently than malignant tumors. However, because of their aggressive growth and poor prognosis, sarcomas must always be considered as a potential differential diagnosis.

Atypical Presentation of a Marjolin Ulcer After a Burn: A Case Report.

The development of a nonhealing ulcer on a chronic wound or scar should raise suspicions of the plastic surgeon or nurse regarding the potential for malignant degeneration to a Marjolin ulcer. Occasionally, a Marjolin ulcer may present as exophytic granulation tissue within a scar. Most Marjolin ulcers are well-differentiated injuries; however, because of their aggressive nature and poor prognosis, to ensure surgical success, diagnosis of Marjolin ulcer should be confirmed and treatment initiated as soon as possible.

Omental free flap for surgical treatment of chronic osteomyelitis of lower limb: A technical note.

Soft tissue reconstruction of chronic lower extremity wounds with bone infection entails an important challenge in reconstructive surgery. We report our experience using the omentum free flap to provide coverage in two patients suffering chronic osteomyelitis of the lower limbs. After extensive soft tissue and bone debridement, an omentum free flap was performed in both cases, providing dead space obliteration and soft tissue coverage in behalf of its large size and pliability.

Correction: Photoswitchable dynasore analogs to control endocytosis with light.

[This corrects the article DOI: 10.1039/D0SC03820B.].

Use of Amniotic Membrane as a Biological Dressing for the Treatment of Torpid Venous Ulcers: A Case Report.

Chronic venous disease manifested as ulcers in the lower limb is a highly prevalent pathology in our population. Antiseptics and dressings designed to improve epithelialization are often used to cure the ulcer during outpatient therapy. Despite careful management, sometimes ulcers do not respond to treatment.

Covalent inactivation of Mycobacterium thermoresistibile inosine-5'-monophosphate dehydrogenase (IMPDH).

Inosine-5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme involved in nucleotide biosynthesis. Because of its critical role in purine biosynthesis, IMPDH is a drug design target for immunosuppressive, anticancer, antiviral and antimicrobial chemotherapy. In this study, we use mass spectrometry and X-ray crystallography to show that the inhibitor 6-Cl-purine ribotide forms a covalent adduct with the Cys-341 residue of Mycobacterium thermoresistibile IMPDH.

A Light-Controlled Allosteric Modulator Unveils a Role for mGlu Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex.

Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses and have become attractive targets for drug therapy to treat certain neurological disorders. However, the high degree of sequence conservation around the glutamate binding site makes the development of subtype-specific orthosteric ligands difficult to achieve.

Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.

Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques.

Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer.

GPCRs play critical roles in cell communication. Although GPCRs can form heteromers, their role in signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical dimers to study the functional interaction between each subunit.

OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity.

OptoGluNAM4.1, a negative allosteric modulator (NAM) of metabotropic glutamate receptor 4 (mGlu4) contains a reactive group that covalently binds to the receptor and a blue-light-activated, fast-relaxing azobenzene group that allows reversible receptor activity photocontrol in vitro and in vivo. OptoGluNAM4.

Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches.

Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1.

Galacto configured N-aminoaziridines: a new type of irreversible inhibitor of β-galactosidases.

A new type of galactose mimetics has been synthesized following a straightforward synthetic approach based on cyclohexene olefin aziridination reactions directed by hydroxyl substituents. These enantiomerically pure galacto-configured N-aminoaziridines are potent irreversible inhibitors of Aspergillus oryzae and Escherichia coliβ-galactosidases.

Synthesis and evaluation of hydroxymethylaminocyclitols as glycosidase inhibitors.

Four series of C7N aminocyclitol analogues of glucose were synthesized by stereocontrolled epoxide opening of hydroxyl protected forms of the cyclohexane epoxides cyclophellitol and 1,6-epi-cyclophellitol. The resulting hydroxymethyl substituted aminocyclitols were tested as glycosidase inhibitors. Cyclitols having an amino group in an α configuration at a position equivalent to the anomeric in the sugar were found to be low micromolar inhibitors of the α-glucosidase from baker's yeast with Ki's near to 2 μM.

Exploring the active conformation of cyclohexane carboxylate positive allosteric modulators of the type 4 metabotropic glutamate receptor.

The active conformation of a family of metabotropic glutamate receptor subtype 4 (mGlu4 ) positive allosteric modulators (PAMs) with the cyclohexane 1,2-dicarboxylic scaffold present in cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041) was investigated by testing structurally similar six-membered ring compounds that have a locked conformation. The norbornane and cyclohexane molecules designed as mGlu4 conformational probes and the enantiomers of the trans diastereomer were computationally characterized and tested in mGlu4 pharmacological assays. The results support a VU0155041 active conformation, with the chair cyclohexane having the aromatic amide substituent in an axial position and the carboxylate in an equatorial position.

Glucocerebrosidase inhibitors for the treatment of Gaucher disease.

Gaucher disease is a progressive lysosomal storage disorder caused by a deficiency in the activity of β-glucocerebrosidase and is characterized by the accumulation of the glycosphingolipid glucosylceramide in the lysosomes of macrophages that leads to dysfunction in multiple organ system. An emerging strategy for the treatment of Gaucher disease is pharmacological chaperone therapy, based on the use of β-glucocerebrosidase inhibitors that are capable of enhancing residual hydrolytic activity at subinhibitory concentrations. In this article, the most common lysosomal storage disorder, Gaucher disease, is introduced and the current therapeutic strategies based on the use of enzyme inhibitors to ameliorate this disease are discussed, with a focus on the efforts being made toward finding and optimizing novel molecules as pharmacological chaperones for Gaucher disease that offer the promise to remedy this malady.