C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound as a potent entry inhibitor lacking cellular toxicity.

Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates.

, the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four l-tryptophan (Trp) units bearing an aromatic isophthalic acid directly attached to the C2 position of each indole ring. Starting from , we (i) replaced l-Trp with d-Trp, (ii) inserted a flexible linker between C2 and the isophthalic acid, and (iii) substituted a nonaromatic carboxylic acid for the terminal isophthalic acid. Truncated analogues lacking the Trp motif were also synthesized.

Organotropic dendrons with high potency as HIV-1, HIV-2 and EV-A71 cell entry inhibitors.

We have recently described a novel family of compounds of reduced size and dual anti-HIV and anti-EV71 activity that encompasses tripodal and tetrapodal derivatives. The tripodal prototype, AL-470, has a nitro group at the focal point of the central scaffold and three attached tryptophan residues, each of which bearing an isophthaloyl moiety at the C2 position of the indole ring. A nitro to amino substitution has allowed us now to introduce a chemically addressable functionality to perform further structural modifications consisting of both direct and linker-mediated attachment of several aromatic groups, including the fluorescent dye Alexa Fluor 647 and the antibody-recruiting 2,4-dinitrophenyl motif.

Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV-1 and EV-A71 Entry Inhibitors†.

We have recently described a new generation of potent human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The prototypes contain three or four tryptophan (Trp) residues bearing an isophthalic acid moiety at the C2 position of each side-chain indole ring. This work is now extended by both shifting the position of the isophthalic acid to C7 and synthesizing doubly arylated C2/C7 derivatives.

Multivalent Tryptophan- and Tyrosine-Containing [60]Fullerene Hexa-Adducts as Dual HIV and Enterovirus A71 Entry Inhibitors.

Unprecedented 3D hexa-adducts of [60]fullerene peripherally decorated with twelve tryptophan (Trp) or tyrosine (Tyr) residues have been synthesized. Studies on the antiviral activity of these novel compounds against HIV and EV71 reveal that they are much more potent against HIV and equally active against EV71 than the previously described dendrimer prototypes AL-385 and AL-463, which possess the same number of Trp/Tyr residues on the periphery but attached to a smaller and more flexible pentaerythritol core. These results demonstrate the relevance of the globular 3D presentation of the peripheral groups (Trp/Tyr) as well as the length of the spacer connecting them to the central core to interact with the viral envelopes, particularly in the case of HIV, and support the hypothesis that [60]fullerene can be an alternative and attractive biocompatible carbon-based scaffold for this type of highly symmetrical dendrimers.

Optical control of muscular nicotinic channels with azocuroniums, photoswitchable azobenzenes bearing two N-methyl-N-carbocyclic quaternary ammonium groups.

By linking two N-methyl-N-carbocyclic quaternary ammonium groups to an azobenzene scaffold in meta- or para-positions we generated a series of photoswitchable neuromuscular ligands for which we coined the term "azocuroniums". These compounds switched between the (E)- and (Z)-isomers by light irradiation at 400-450 nm and 335-340 nm, respectively. Meta-azocuroniums were potent nicotinic ligands with a clear selectivity for the muscular nAChRs compared to neuronal α7 and α4β2 subtypes, showed good solubility in physiologic media, negligible cell toxicity, and would not reach the CNS.

Tryptophan Trimers and Tetramers Inhibit Dengue and Zika Virus Replication by Interfering with Viral Attachment Processes.

Here, we report a class of tryptophan trimers and tetramers that inhibit (at low micromolar range) dengue and Zika virus infection These compounds (AL family) have three or four peripheral tryptophan moieties directly linked to a central scaffold through their amino groups; thus, their carboxylic acid groups are free and exposed to the periphery. Structure-activity relationship (SAR) studies demonstrated that the presence of extra phenyl rings with substituents other than COOH at the N1 or C2 position of the indole side chain is a requisite for the antiviral activity against both viruses. The molecules showed potent antiviral activity, with low cytotoxicity, when evaluated on different cell lines.

Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors.

Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. The situation is even worse for enterovirus EV71 infection for which no antiviral therapies are available. We describe here the discovery of potent entry dual inhibitors of HIV and EV71.

Modifications in the branched arms of a class of dual inhibitors of HIV and EV71 replication expand their antiviral spectrum.

We have previously reported a new class of dendrimers with tryptophan (Trp) residues on the surface that show dual antiviral activities against HIV and enterovirus EV71. The prototype compound of this family is a derivative of pentaerythritol with 12 peripheral Trp groups and trivalent spacer arms. Here a novel series of dendrimers with divalent and tetravalent branched arms, instead of the trivalent ones present on the prototype, has been synthesized and its activity against HIV, EV71 and a panel of 16 different viruses and other pathogens has been determined.

Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases.

The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis.