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Crystallophores are lanthanide complexes that have demonstrated outstanding induction of crystallization for various proteins. This article explores the effect of tailored modifications of the crystallophore first generation and their impact on the nucleating properties and protein crystal structures. Through high-throughput crystallization experiments and dataset analysis, we evaluated the effectiveness of these variants, in comparison to the first crystallophore generation G 1 . In particular, the V 1 variant, featuring a propanol pendant arm, demonstrated the ability to produce new crystallization conditions for the proteins tested (hen-egg white lysozyme, proteinase K and thaumatin). Structural analysis performed in the case of hen egg-white lysozyme along with Molecular Dynamics simulations, highlights V 1 's unique behavior, taking advantage of the flexibility of its propanol arm to explore different protein surfaces and form versatile supramolecular interactions., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

This work investigates the electron-donating capabilities of two 10-π electron nitrogen bridgehead bicyclic [5,6]-fused ring systems, imidazo[1,2- a ]pyridine and imidazo[1,5- a ]pyridine rings. Eight compounds with varying positions of electron-withdrawing moieties (TCF or DCI) coupled to the imidazopyridine ring were synthesized and studied. DCI-containing compounds ( Ib - IVb ) exhibited a purely dipolar nature with broad absorption bands, weak fluorescence, large Stokes shifts, and strong solvatochromism. In contrast, TCF-containing compounds ( Ia - IVa ) demonstrated diverse properties. Imidazo[1,2- a ]pyridine derivatives Ia and IIa were purely dipolar, while imidazo[1,5- a ]pyridine derivatives IIIa and IVa displayed a cyanine-like character with intense absorption and higher quantum yields of emission. The observed gradual red shift in optical properties with changing electron-donor groups ( IIb < Ib < IIIb < IVb ) and ( IIa < Ia < IIIa < IVa ) underscores the stronger electron-donor character of imidazo[1,5- a ]pyridine compared to that of imidazo[1,2- a ]pyridine. Furthermore, crystalline powders of imidazo[1,2- a ]pyridine derivatives exhibited fluorescence despite minimal emission in solution. Two compounds ( Ib and IVa ) were successfully formulated into nanoparticles for potential in vivo imaging applications in zebrafish embryos.

Copolymer thin films showing induced supramolecular chirality are of considerable interest for optoelectronic applications such as organic light-emitting diodes. Here, we introduce a new helicene-like chiral additive with two octyloxy substituents which displays excellent chiral induction properties in an achiral polyfluorene copolymer, leading to a circular dichroism (CD) response of up to 10,000 mdeg. This chiral inducer also displays very good thermal stability, which enables us to perform an extended study on the induced chiroptical properties of the cholesteric copolymer thin films annealed at different temperatures in the range 140-260 °C. Starting from about 180 °C, a distinct change in the morphology of the CD-active film is observed by CD microscopy, from micrometre-size granular to extended CD-active regions, where the latter ones display skewed distributions of the dissymmetry parameter g abs . Broadband Müller matrix spectroscopy finds a pronounced CD and circular birefringence (CB) response and only weak linear dichroism (LD, LD') and linear birefringence (LB, LB'). Ultrafast transient CD spectroscopy with randomly polarised excitation reveals a clean mirror-image-type transient response, which shows a second-order decay of the S 1 population due to singlet-singlet annihilation processes., (© 2024. The Author(s).)

Cryptophane molecules are cage-like structures consisting in two hemispheres, each made of three benzene rings. These hemispheres are bound together with three O(CH 2 ) n Olinkers of various lengths giving rise to a plethora of cryptophane derivatives. Moreover, they are able to encapsulate neutral guests: CH 2 Cl 2 , CHCl 3 , …; and charged species: Cs + , Tl + , …. Finally, they exhibit chiroptical properties thanks to the anti arrangement of the linkers between the hemispheres. This work focuses on the Raman optical activity (ROA) signatures of Cryptophane-111 (n=1 for each linker). More specifically, we aim at simulating accurately its ROA spectra with and without a xenon atom inside its cavity. Experimental data (Buffeteau et al., 2017) have already demonstrated the effect of the encapsulation in the low-wavenumbers region. To generate the initial structures, we rely on the novel Conformer-Rotamer Ensemble Sampling Tool (CREST) program, developed by S. Grimme and co-workers. This is required due to the flexibility provided by the linkers. The CREST algorithm seems promising and has already been used to sample the potential energy surface (PES) of target systems before the simulation of their vibrational spectroscopies (Eikås et al., 2022). We observe large similarities between the two sets of conformers (one with and one without Xe encapsulated), demonstrating the robustness of the CREST algorithm. For corresponding structures, the presence of xenon pushed the two hemispheres slightly further apart. After optimization at the DFT level, only one unique conformer has a Boltzmann population ratio greater than 1%, pointing out the relative rigidity of the cage. Based on this unique conformer, our simulations are in good agreement with the experimental data. Regarding xenon encapsulation, the (experimental and theoretical) ROA signatures at low wavenumbers are impacted: slight shifts in wavenumbers are observed as well as a decrease in relative ROA intensity for bands around 150 cm -1 . The wavenumber shifts were very well reproduced by our simulations, but the experimental decrease in the ROA intensity was unfortunately not reproduced., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A series of molecules that possess two quinolines, benzoquinolines, or phenanthrolines connected in a chiral fashion by a biaryl junction along with their water-soluble derivatives was developed and characterized. The influence of the structure on the basicity of the nitrogen atoms in two heterocycles was examined and the photophysical and chiroptical switching activity of the compounds upon protonation was studied both experimentally and computationally. The results demonstrated that changes in the electronic structure of the protonated vs. neutral species, promoting a bathochromic shift of dominant electronic transitions and alternation of their character from π-to-π* to charge-transfer-type, when additionally accompanied by the high structural flexibility of a system, leading to changes in conformational preferences upon proton binding, produce particularly pronounced modifications of the spectral properties in acidic medium. The latter combined with reversibility of the read-out make some of the molecules in this series very promising multifunctional pH probes.

Organic molecules have been intensively studied during the last few decades because of their photonics and biological applications. In this material class, the fluorene molecules present outstanding optical features, for example, high values of two-photon absorption (2PA) cross-sections, visible transparency, and high fluorescence quantum yield. Also, it is possible to improve the nonlinear optical response by modifying the fluorene molecular structure. In this context, herein, we have synthesized V and Y-shaped branching oligofluorenes containing two and three fluorene moieties in each branch. Such a molecular strategy may exponentially enhance the nonlinear optical response due to the coherent coupling among the molecular arms. Thus, we combined the use of femtosecond Z-scan spectroscopy and white light transient absorption spectroscopy (TAS) to understand the molecular structure and 2PA property relationship of branching oligofluorenes. The results show that there is a universal relationship between the 2PA cross-section and the effective π-electron number ( N eff ) given by σ 2PA (GM) = (079 ± 0.03) N eff 2 , which is independent of the molecular shape (linear, V or Y-shaped). Therefore, the intramolecular charge transfer responsible for the cooperative effect among the branches does not occur. This statement is corroborated by the results of the femtosecond TAS technique.

Cysteine (Cys) is subject to a variety of reversible post-translational modifications such as formation of sulfenic acid (Cys-SOH). If this modification is often involved in normal biological activities, it can also be the result of oxidative damage. Indeed, oxidative stress yields abnormal cysteine oxidations that affect protein function and structure and can lead to neurodegenerative diseases. In a context of population ageing, validation of novel biomarkers for detection of neurodegenerative diseases is important. However, Cys-SOH proteins investigation in large human cohorts is challenging due to their low abundance and lability under endogenous conditions. To improve the detection specificity towards the oxidized protein subpopulation, we developed a method that makes use of a mass spectrometer coupled with visible laser induced dissociation (LID) to add a stringent optical specificity to the mass selectivity. Since peptides do not naturally absorb in the visible range, this approach relies on the proper chemical derivatization of Cys-SOH with a chromophore functionalized with a cyclohexanedione. To compensate for the significant variability in total protein expression within the samples and any experimental bias, a normalizing strategy using free thiol (Cys-SH) cysteine peptides derivatized with a maleimide chromophore as internal references was used. Thanks to the differential tagging, oxidative ratios were then obtained for 69 Cys-containing peptides from 19 proteins tracked by parallel reaction monitoring (PRM) LID, in a cohort of 49 human plasma samples from Alzheimer disease (AD) patients. A statistical analysis indicated that, for the proteins monitored, the Cys oxidative ratio does not correlate with the diagnosis of AD. Nevertheless, the PRM-LID method allows the unbiased, sensitive and robust relative quantification of Cys oxidation within cohorts of samples., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fluorene-based molecules exhibit significant nonlinear optical responses and multiphoton absorption in the visible region, which, combined with the high fluorescence quantum yield in organic solvents, could make this class of materials potentially engaging in diverse photonics applications. Thus, herein, we have determined the two-photon absorption (2PA) of oligofluorenes containing three, five, and seven repetitive units by employing the wavelength-tunable femtosecond Z-scan technique. Our outcomes have shown that the 2PA cross-section in oligofluorenes presents an enhanced value of around 18 GM per N eff , in which N eff is the effective number of π-electrons, for the pure 2PA allowed transition (1 1 A g -like → 2 1 A g -like). Furthermore, a weak 2PA transition was observed in the same spectral region strongly allowed by one-photon absorption (1 1 A g -like → 1 1 B u -like). This last result suggests a molecular symmetry perturbation, probably induced by the molecular disorder triggered by the increase of moieties in the oligofluorene structure. We have calculated the permanent dipole moment difference related to the lowest-energy transition using the Lippert-Matagaformalism and the 2PA sum-over-states approach to confirm this assumption. Moreover, we have estimated the fundamental limits for the 2PA cross-section in oligofluorenes.

Cysteine (Cys) is prone to diverse post-translational modifications in proteins, including oxidation into sulfenic acid (Cys-SOH) by reactive oxygen species generated under oxidative stress. Detection of low-concentration and metastable Cys-SOH within complex biological matrices is challenging due to the dynamic concentration range of proteins in the samples. Herein, visible laser-induced dissociation (LID) implemented in a mass spectrometer was used for streamlining the detection of Cys oxidized proteins owing to proper derivatization of Cys-SOH with a chromophore tag functionalized with a cyclohexanedione group. Once grafted, peptides undergo a high fragmentation yield under LID, leading concomitantly to informative backbone ions and to a chromophore reporter ion. Seventy-nine percent of the Cys-containing tryptic peptides derived from human serum albumin and serotransferrin tracked by parallel reaction monitoring (PRM) were detected as targets subjected to oxidation. These candidates as well as Cys-containing peptides predicted by in silico trypsin digestion of five other human plasma proteins were then tracked in real plasma samples to pinpoint the endogenous Cys-SOH subpopulation. Most of the targeted peptides were detected in all plasma samples by LID-PRM, with significant differences in their relative amounts. By eliminating the signal of interfering co-eluted compounds, LID-PRM surpasses conventional HCD (higher-energy collisional dissociation)-PRM in detecting grafted Cys-SOH-containing peptides and allows now to foresee clinical applications in large human cohorts.

We report in this article the synthesis of an asymmetrical cryptophane derivative (possessing only C 3 -symmetry) bearing three phenol groups and three other carboxylic acid functions, each of these groups on the aromatic rings. Thanks to isothermal titration calorimetry experiments, we show that this compound binds large monovalent cations, such as Cs + and Tl + , with a binding constant significantly lower than its congeners bearing a larger number of phenol groups grafted on the benzene rings. However, higher selectivity for Cs + and Tl + was observed with this compound since it does not show any affinity for other alkali cations. More importantly, due to the greater solubility of this derivative in pure water, we show for the first time that effective thallium(I) complexation takes place at neutral pH. This result demonstrates that cryptophane derivatives decorated with a higher number of phenol groups are promising host molecules for removing traces of thallium(I) from aqueous phases at neutral pH or above.

We report on the synthesis of C 3 -symmetric enantiopure cage molecules 1 , which exhibit remarkable to exclusive enantioselective recognition properties toward chiral ammonium neurotransmitters. Strong changes in the substrate selectivity are also observed when different stereoisomers of 1 are used. Furthermore, protonation/deprotonation induces a reversible modification of the conformation of 1 , which switches from an imploded to an inflated form, leading to ejection and reuptake of the guest initially encaged inside the cavity.

We describe a large-scale synthesis of a series of helicene-like compounds based on a dibenzo[ c ]acridine fragment by the Friedlander reaction. The series includes targeted constrained (closed) derivatives comprising 11 rings that exhibit very intense circularly polarized luminescence (CPL) ( g lum = 8 × 10 -3 ) contrary to their nonconstrained (open) 10-ring precursors that are not CPL active. The relationship between structure and chiroptical properties in the series is discussed with the aid of quantum-chemical calculations.

Whereas the synthesis of the anti-cryptophane-A (1) derivative has been known for nearly 40 years, the preparation of its diastereomer (cryptophane-B according to Collet's nomenclature) has never been reported. Thus, the synthesis of the cryptophane-B derivative represents a real challenge for chemists interested in the preparation of these hollow molecules. Herein, we describe a synthetic route that allows us to prepare cryptophane-B (2), albeit in a low yield. The X-ray crystallographic structure of this compound is described, and it reveals the presence of an ethanol molecule inside the cavity of the host. Finally, the ability of cryptophane-B to bind xenon in 1,1,2,2-tetrachloroethane- d 2 is also studied via hyperpolarized 129 Xe NMR.

In the search for powerful non-invasive methods for pH measurement, NMR usually suffers from biases, especially for heterogeneous samples or tissues. In this Communication, using the signals of hyperpolarized 129 Xe encapsulated in a pair of water-soluble cryptophanes, we show that a differential pH measurement can be achieved, free from most of these biases, by monitoring the difference between their chemical shifts., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Macromolecular crystallography suffers from two major issues: getting well-diffracting crystals and solving the phase problem inherent to large macromolecules. Here, we describe the first example of a lanthanide complex family named "crystallophore" (Xo4), which contributes to tackling both bottlenecks. This terbium complex, Tb-Xo4, is an appealing agent for biocrystallography, combining the exceptional phasing power of the Tb(iii) heavy atom with powerful nucleating properties, providing ready-to-use crystals for structure determination. Furthermore, protein/Tb-Xo4 co-crystals can be easily detected and discriminated from other crystalline by-products using luminescence. We demonstrate the potential of this additive for the crystallisation and structure determination of eight proteins, two of whose structures were unknown.

The two enantiomers of cryptophane-111 (1), which possesses the most simplified chemical structure of cryptophane derivatives and exhibits the highest binding constant for xenon encapsulation in organic solution, were separated by HPLC using chiral stationary phases. The chiroptical properties of [CD(+) 254 ]-1 and [CD(-) 254 ]-1 were determined in CH 2 Cl 2 and CHCl 3 solutions by polarimetry, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) experiments and were compared to those of cryptophane-222 (2) derivative. Synchroton Radiation Circular Dichroism (SRCD) spectra were also recorded for the two enantiomers of 1 to investigate low-lying excited states in the 1 B b region. Time-dependent density functional theory (TDDFT) calculations of the ECD and SRCD as well as DFT calculations of the VCD and ROA allowed the [CD(-) 254 ]-PP-1 and [CD(+) 254 ]-MM-1 absolute configurations for 1 in CH 2 Cl 2 and CHCl 3 solutions. Similar configurations were found in the solid state from X-ray crystals of the two enantiomers but the chemical structures are significantly different from the one calculated in solution. In addition, the chiroptical properties of the two enantiomers of 1 were independent of the nature of the solvent, which is significantly different to that observed for cryptophane-222 compound. The lack of solvent molecule (CH 2 Cl 2 or CHCl 3 ) within the cavity of 1 can explain this different behaviour between 1 and 2. Finally, we show in this article that the encapsulation of xenon by 1 can be evidenced by ROA following the symmetric breathing mode of the cryptophane-111 skeleton at 150 cm -1 .

The synthesis, characterization, and chiroptical properties of a new class of hemicryptophane cages combining a cyclotriveratrylene unit and a tris(2-pyridylmethyl)amine (TPA) moiety are reported. Changing the linkers between these two units allows for the modification of the size and shape of the cavity. The synthesis is straightforward and efficient, providing gram-scale of cage compounds. The racemic mixture of each hemicryptophane host can be readily resolved by chiral HPLC, giving an easy access to the enantiopure molecular cages of which absolute configurations have been assigned by ECD spectroscopy. These new hemicryptophanes are available chemical platforms ready to use for various purposes due to the versatile metal complexation properties of the TPA unit. A Zn(II)@hemicryptophane complex has been obtained and used as a heteroditopic host for the selective recognition of zwitterionic guests.

The origin of ancient ligand/receptor couples is often analyzed via reconstruction of ancient receptors and, when ligands are products of metabolic pathways, they are not supposed to evolve. However, because metabolic pathways are inherited by descent with modification, their structure can be compared using cladistic analysis. Using this approach, we studied the evolution of steroid hormones. We show that side-chain cleavage is common to most vertebrate steroids, whereas aromatization was co-opted for estrogen synthesis from a more ancient pathway. The ancestral products of aromatic activity were aromatized steroids with a side chain, which we named "paraestrols." We synthesized paraestrol A and show that it effectively binds and activates the ancestral steroid receptor. Our study opens the way to comparative studies of biologically active small molecules.

Enantiopure cryptophane-222 derivative (1) devoid of substituents was obtained via high-performance liquid chromatography (HPLC) using chiral stationary phases. The chiroptical properties of 1 were determined from polarimetry, electronic circular dichroism (ECD), synchrotron radiation circular dichroism (SRCD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) experiments and were compared to those of the cryptophane-A (2) derivative. Unusual polarimetric results were obtained for 1 in CHCl 3 solvent as the sign of the optical rotation (OR) values changes in the nonresonance region above 365 nm, whereas no change was observed in the CH 2 Cl 2 solvent. ECD spectra in the 1 L a and 1 L b regions were very similar for the two solutions and could not explain these unusual polarimetric properties. In contrast, SRCD spectra in the 1 B b region revealed spectral differences for the two solutions, which have been associated with conformational changes of the three linkers by time-dependent density functional theory (TDDFT) calculations. DFT calculations of the OR support that conformational changes may explain the polarimetric results obtained for the two solvents. Finally, TDDFT calculations of the ECD as well as DFT calculations of the VCD and ROA allowed the attribution of the (-) 589 -PP absolute configuration for 1 in solution, as determined from the X-ray structures of 1.

We report the synthesis, spectroscopy, and the DNA binding properties of a biocompatible, water-soluble, polycationic two-photon absorbing anthracenyl derivative (Ant-PIm) specifically designed for biorelated applications. Detailed insights into the Ant-PIm-DNA binding interaction are provided by using several spectroscopic approaches, including UV-vis absorption, circular dichroism (CD), Fourier-transform infrared spectroscopy (FTIR), steady-state, and time-resolved fluorescence techniques. Absorption and fluorescence quantitative data analysis show a strong Ant-PIm-duplex interaction with binding constants of K f = 4.7 ± 0.2 × 10 5 M -1 , 7.1 ± 0.3 × 10 5 M -1 , and 1.0 ± 0.1 × 10 6 M -1 at 298, 304, and 310 K, respectively. Spectral changes observed upon DNA binding provide evidence for a complex formation with off-on fluorescence pattern, which can be related to two consecutive binding equilibria. Results of DNA binders displacement and iodide quenching experimental assays unambiguously point to the groove binding mode of Ant-PIm to the DNA-helicate. Thermodynamic and chemical denaturation studies suggest that long-range interactions of hydrophobic nature regulate the association of Ant-PIm with the biopolymer. The ionic strength dependence of the binding constant shows that electrostatic component has an important contribution to the overall Gibbs free energy. FTIR and CD data provide evidence of partial modification of the B-DNA secondary structure, while the increase in the melting temperature clearly indicates the enhancement of the thermal stability of the duplex. Furthermore, the two-photon absorption cross section spectrum determined using the two-photon excited fluorescence (TPEF) technique shows a strong 2PA maximum at 820 nm with a σ 2 > 800 GM, which emphasizes the advantageous combination of biological and optical properties possessed by this positively charged bioprobe.

New host compounds combining a cyclotriveratrylene (CTV) unit and three binaphthol moieties have been synthesized enantiomerically and diastereomerically pure. The use of a chemical correlation allows for the assignment of their absolute configuration. The energy barrier of epimerization was measured, suggesting that no intramolecular hydrogen bonding occurs between the hydroxyl groups of the binaphthols. These open-shell host compounds were then tested in the recognition of carbohydrates; a preferential binding of mannose toward glucose was observed, and good diastereoselectivities were reached (up to 1:10). This recognition of sugar derivatives by open-shell CTV-based host compounds is unprecedented and opens up the way for a wider use of this easily accessible class of molecules as chiral sensors.

Helicenes are fascinating molecules owing to their unusual properties and applications in many fields from catalysis to organic electronics. Herein, we report a straightforward pathway for the synthesis of helicene-like molecules on a gram scale in an enantiopure form. Thin-film materials with good propagating optical properties and very high chiroptical responses have been grown by using pulsed laser ablation without altering the structure or the enantiopurity of the molecules. Moreover, electronic and vibrational circular dichroism spectroscopies coupled with theoretical calculations enabled some dependences of the chiroptical properties with the structure to be highlighted, for example, effects of rigidification, aromatization, or the state of matter (liquid versus solid)., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have studied the interaction of a polymeric water soluble anthracenyl derivative () with salmon testes DNA. The results from UV-Vis, fluorescence, Fourier transform infrared (FT-IR) and circular dichroism spectroscopies indicate that the groove binding process regulates the interaction between and DNA. The binding constants, calculated by absorption spectroscopy at 298, 304 and 310 K, were equal to 3.2 × 10(5) M(-1), 4.7 × 10(5) M(-1), and 6.6 × 10(5) M(-1) respectively, proving a relatively high affinity of for salmon testes DNA. Results of Hoechst 33258 displacement assays strongly support the groove binding mode of to DNA. The association stoichiometry of the :DNA adduct was found to be 1 for every 5 base pairs. FT-IR spectra, recorded at different /DNA molar ratios, indicate the involvement of the phosphate groups and adenine and thymine DNA bases in the association process. Thermodynamic results suggest that hydrophobic forces regulate the binding of with DNA without excluding some extent of involvement of van der Waals forces and hydrogen bonding arising due to surface binding between the hydrophilic polymeric arms of the ligand and the functional groups positioned on the edge of the groove. The resulting composite biomaterial could constitute a valuable candidate for future biological and/or photonic applications.

During the course of our research studies aiming to combine the unique photophysical properties of lanthanide complexes and the intrinsic advantage of a nonlinear two-photon excitation, we described the proof-of-concept of a biphotonic multiplexing bio-imaging experiment. To that end, a new Tb-luminescent bioprobe [TbL(2)] was designed using the TACN-trispicolinate platform. The biphotonic imaging of T24 fixed cells stained either with [TbL(2)] or with the already described [EuL(1)] complexes is reported. Finally the biphotonic multiplexing experiment was performed using a combination of both probes using the spectral mode of the two-photon microscope.

To create novel HIV-1 protease (HIV PR) inhibitors, we have extended our investigations of the N-->C=O interaction as a moiety that reproduces electrostatic properties of the transition state of peptidolysis. Consequently, we prepared a series of compounds with an unusual hydrazino-urea core. In polar protic media, these adopt solely a cyclic constitution displaying the interaction on one side of the molecule while offering a urea moiety on the opposite side meant to hydrogen-bond with the enzyme flaps. Each inhibitor candidate was obtained via a key series of three synthetic steps employing carbonyl-di-imidazole (CDI). It was thus possible to efficiently fuse two independent building blocks, a hydrazine and a protected aminoaldehyde in a convergent manner. NMR and UV analysis proved that all compounds, when dissolved in polar protic media, existed exclusively in the cyclic constitution exhibiting the N-->C=O interaction. In total, five inhibitor candidates were tested with HIV PR for their potency. The one carrying the least bulk in peripheral substituents showed the highest activity. Its very low molecular weight (365 g/mol) holds great promise for future improvements in affinity without violating Lipinski's rule of remaining within the limit of 500 g/mol.

The donor-acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloids, was deliberately established in a peptidomimetic (1a-c) to mimic features of the two principal transition states of peptide hydrolysis. Compounds 1a-c show preferential adoption in methanol and water of a 'folded' conformation displaying the interaction. Proportions of the folded form in MeOH range from 45% to 70% and can reach 84% in buffer. Significantly, three tendencies for the folded/unfolded equilibrium are observed: increasing solubility and polarity of the medium and decreasing temperature results in a higher extent of folding. In the absence of any parameter set available for this weak bond, no modeling studies were conducted to aid in the design of 1a-c. The successful straightforward synthesis of 1 and its folding and inhibition results with HIV-1 peptidase using FRET technology encourage studies to further pre-organize candidate molecules and to screen the structure space by modeling and parallel combinatorial chemistry.