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COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human coronavirus (hCoV) that spreads among humans and animals. Great efforts have been made to develop therapeutic agents to treat COVID-19, and among the available viral molecular targets, the cysteine protease SARS-CoV-2 M pro is considered the most appealing one due to its essential role in viral replication. However, the inhibition of M pro activity is an interesting challenge and several small molecules and peptidomimetics have been synthesized for this purpose. In this work, the Michael acceptor cinnamic ester was employed as an electrophilic warhead for the covalent inhibition of M pro by endowing some peptidomimetic derivatives with such a functionality. Among the synthesized compounds, the indole-based inhibitors 17 and 18 efficiently impaired the in vitro replication of beta hCoV-OC-43 in the low micromolar range (EC 50 = 9.14 μM and 10.1 μM, respectively). Moreover, the carbamate derivative 12 showed an antiviral activity of note (EC 50 = 5.27 μM) against another hCoV, namely hCoV-229E, thus suggesting the potential applicability of such cinnamic pseudopeptides also against human alpha CoVs. Taken together, these results support the feasibility of considering the cinnamic framework for the development of new M pro inhibitors endowed with antiviral activity against human coronaviruses.

Addition of azobenzene-derivative 1 in its E configuration to an aqueous solution containing various guanosine borate esters induces a helical G-quartet based self-organization, stabilized by intercalation of the dye. The process is driven, in a domino fashion, by the initial host-guest interaction between the dye and a specific guanosine borate diester, whose structure can be thus assigned. This inclusion complex templates the formation of G-quartets. The quartets, in turn, pile up to form a supramolecular G-quadruplex structure, in which other G species present in solution are progressively included. The G-quadruplex can be reversibly broken and reformed by photoisomerization of the dye. This hierarchical and photosensitive self-assembly is unprecedented for simple guanosine derivatives.

Small and easy-to-do mimetics of β-turns are of great interest to interfere with protein-protein recognition events mediated by β-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd(2)-Oxd(3) or ΔAbu(2)-Oxd(3) (Oxd, oxazolidin-2-one; ΔAbu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained ϕ, ψ, and χ dihedral angles, and induced clear β-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses.

Axially chiral, 3,5-dihydro-4H-dinaphtho[2,1-c:1',2'-e]azepine (dinaphthazepine) and 1,1'-binaphthyl-2,2'-disulfonimide (dinaphthosulfonimide) moieties were rigidly connected via N-p-phenylene linkers to photochemically (E)/(Z)-isomerisable 1,2-diethynylethene scaffolds. The chemical stability of the resulting systems was found to be critically related to the other substituents on the central π-conjugated scaffold. High helical twisting power (HTP), up to 315 μm(-1), for the induction of a cholesteric liquid-crystalline phase through doping of a nematic phase was measured, resulting from the introduction of the chiral, mesogenic 1,1'-binaphthyl motifs. Single crystal X-ray analysis revealed that the phenylene spacer is in π-conjugation with the N-atom of the dinaphthazepine but not with the N-atom of the dinaphthosulfonimide moiety. This difference in orientation results in visible-transparency in the electronic absorption spectrum and higher (E)/(Z)-photoisomerisation quantum yields of the dinaphthosulfonimide-derived chiral dopants, as compared to the dinaphthazepine systems, which feature intramolecular charge-transfer absorption in the visible region.

G-quadruplex DNA (G4-DNA) structures are four-stranded helical DNA (or RNA) structures, comprising stacks of G-tetrads, which are the outcome of planar association of four guanines in a cyclic Hoogsteen hydrogen-bonding arrangement. In the last decade the number of publications where CD spectroscopy has been used to study G4-DNAs, is extremely high. However, with very few exceptions, these investigations use an empirical interpretation of CD spectra. In this interpretation two basic types of CD spectra have been associated to a single specific difference in the features of the strand folding, i.e. the relative orientation of the strands, "parallel" (all strands have the same 5' to 3' orientation) or "antiparallel". Different examples taken from the literature where the empirical interpretation is not followed or is meaningless are presented and discussed. Furthermore, the case of quadruplexes formed by monomeric guanosine derivatives, where there is no strand connecting the adjacent quartets and the definition parallel/antiparallel strands cannot apply, will be discussed. The different spectral features observed for different G-quadruplexes is rationalised in terms of chromophores responsible for the electronic transitions. A simplified exciton coupling approach or more refined QM calculations allow to interpret the different CD features in terms of different stacking orientation (head-to-tail, head-to-head, tail-to-tail) between adjacent G-quartets irrespectively of the relative orientation of the stands (parallel/antiparallel).

We report here our findings on a lipophilic guanosine derivative armed with a terthiophene unit that undergoes a pronounced variation of its supramolecular organisation by changing the polarity of the solvent. In chloroform the guanosine derivative, templated by alkali metal ions, assembles via H-bonding in G-quartet based D(4)-symmetric octamers; the polar guanine bases are located into the inner part of the assembly and act as a scaffold for the terthienyl pendants. On the other hand, in the more polar (and H-bond competing) acetonitrile, different aggregates are observed in which the terthiophene chains are pi-pi stacked in a helicoidal (left-handed) arrangement in the central core, and the guanine bases (free from hydrogen bonding) are located at the periphery and exposed to the solvent. The system can be switched back and forth by subsequent addition of chloroform and acetonitrile. The solvent-induced switching can be easily followed by circular dichroism spectroscopy: the CD exciton-couplet in the guanine chromophore absorption region observed in chloroform disappears after addition of acetonitrile, indicating the disassembly of the G-quartet based octameric structure, while an intense quasi-conservative exciton splitting in the 300-450 nm spectral region becomes predominant in the CD spectrum. This latter strong bisignate optical activity can be ascribed to the helical packing of conjugated terthiophene moieties stabilised by pi-pi interactions. NMR spectra and photophysical investigations confirm the structures of the guanine-directed and thiophene-directed assemblies in chloroform and acetonitrile, respectively.