ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties.

Tenofovir (TFV) is the cornerstone nucleotide reverse transcriptase inhibitor (NtRTI) in many combination antiretroviral therapies prescribed to patients living with HIV/AIDS. Due to poor cell permeability and oral bioavailability, TFV is administered as one of two FDA-approved prodrugs, both of which metabolize prematurely in the liver and/or plasma. This premature prodrug processing depletes significant fractions of each oral dose and causes toxicity in kidney, bone, and liver with chronic administration. Although TFV exalidex (TXL), a phospholipid-derived prodrug of TFV, was designed to address this issue, clinical pharmacokinetic studies indicated substantial hepatic extraction, redirecting clinical development of TXL toward HBV. To circumvent this metabolic liability, we synthesized and evaluated ω-functionalized TXL analogues with dramatically improved hepatic stability. This effort led to the identification of compounds 21 and 23, which exhibited substantially longer t1/2 values than TXL in human liver microsomes, potent anti-HIV activity in vitro, and enhanced pharmacokinetic properties in vivo.

Tandem Suzuki Coupling/Intramolecular Oxetane Ring Opening to Form Polycyclic Ring Systems.

A tandem one-pot reaction featuring a cross-coupling followed by an intramolecular oxetane ring opening by mild nucleophiles is reported. The overall transformation comprises a carbon-carbon bond formation along with a carbon-heteroatom bond construction providing diverse multicyclic ring systems with a pendant hydroxymethyl handle for further elaboration. This approach constitutes a convergent method for rapid access to various scaffolds. Furthermore, a comparison of computed low-energy conformers is presented to rationalize instances in which cyclization was not observed.

Accelerated Discovery of Potent Fusion Inhibitors for Respiratory Syncytial Virus.

A series of five benzimidazole-based compounds were identified using a machine learning algorithm as potential inhibitors of the respiratory syncytial virus (RSV) fusion protein. These compounds were synthesized, and compound 2 in particular exhibited excellent in vitro potency with an EC50 value of 5 nM. This new scaffold was then further refined leading to the identification of compound 44, which exhibited a 10-fold improvement in activity with an EC50 value of 0.5 nM.

Gating control of the cardiac sodium channel Nav1.5 by its ß3-subunit involves distinct roles for a transmembrane glutamic acid and the extracellular domain.

The auxiliary ß3-subunit is an important functional regulator of the cardiac sodium channel Nav1.5, and some ß3 mutations predispose individuals to cardiac arrhythmias. The ß3-subunit uses its transmembrane α-helix and extracellular domain to bind to Nav1.5. Here, we investigated the role of an unusually located and highly conserved glutamic acid (Glu-176) within the ß3 transmembrane region and its potential for functionally synergizing with the ß3 extracellular domain (ECD). We substituted Glu-176 with lysine (E176K) in the WT ß3-subunit and in a ß3-subunit lacking the ECD. Patch-clamp experiments indicated that the E176K substitution does not affect the previously observed ß3-dependent depolarizing shift of V½ of steady-state inactivation but does attenuate the accelerated recovery from inactivation conferred by the WT ß3-subunit. Removal of the ß3-ECD abrogated both the depolarizing shift of steady-state inactivation and the accelerated recovery, irrespective of the presence or absence of the Glu-176 residue. We found that steady-state inactivation and recovery from inactivation involve movements of the S4 helices within the DIII and DIV voltage sensors in response to membrane potential changes. Voltage-clamp fluorometry revealed that the E176K substitution alters DIII voltage sensor dynamics without affecting DIV. In contrast, removal of the ECD significantly altered the dynamics of both DIII and DIV. These results imply distinct roles for the ß3-Glu-176 residue and the ß3-ECD in regulating the conformational changes of the voltage sensors that determine channel inactivation and recovery from inactivation.