Maosheng Cheng

A novel type of N-formylation and related reactions of amines via cyanides and esters as formylating agents.

A novel N-formylation and related reactions proceed from cyanides promoted by esters.

Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket.

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell–cell fusion and infection.

Breaking the conservation of guanine residues in the catalytic loop of 10–23 DNAzyme by position-specific nucleobase modifications for rate enhancement

10-23 DNAzyme has been used as a very good model for exploring the potential of functional nucleic acids. Its 15-mer catalytic core has been demonstrated to be the optimized in vitro selection result. However, with the introduction of protein-like functional groups through 2-deoxyguanosine analogues, its two highly conserved guanine residues (G2 and G14) can be modified for more efficient 10-23 DNAzyme analogues. This result implies that chemical modifications of functional nucleic acids with well-designed nucleoside analogues of each canonical residue could be used as the first step in the efforts toward more powerful functions of nucleic acids.

Hydrophobic mutations in buried polar residues enhance HIV-1 gp41 N-terminal heptad repeat-C-terminal heptad repeat interactions and C-peptides' anti-HIV activity.

Objective:To investigate the effect of mutations in a highly conserved buried polar area on the function of HIV-1 gp41. Design:During HIV-1 entry, a six helical bundle (6-HB) formation between the C-terminal and N-terminal heptad repeat (CHR and NHR) of gp41 provides energy for virus cell membrane fusion. In 6-HB, residues at a and d (a–d) positions of CHR directly interact with NHR and are buried. They are considered critical residues for 6-HB stability and for anti-HIV-1 activity of CHR-derived peptides (C-peptides). Most of a–d residues in CHR are hydrophobic, as buried hydrophobic residues facilitate protein stability. However, HIV-1 gp41 CHR contains a highly conserved polar area with four successive buried a–d polar residues: S649/Q652/N656/E659. We mutated these buried polar residues to hydrophobic residues, either Leu or Ile, and studied its effect on the gp41 NHR–CHR interactions and anti-HIV activities of the C-peptides. Methods:We measured the C-peptide mutants’ ability to form 6-HB with NHR, thermal stability of the 6-HBs and C-peptides’ inhibitory activity against both T20-sensitive and resistant HIV-1 strains. Results:All the mutated C-peptides retained their ability to form stable 6-HB with NHR and strongly inhibited HIV-1 replication. Strikingly, S649L and E659I mutations endow C-peptide with a significantly enhanced activity against T20-resistant HIV-1 strains. Conclusion:The highly conserved buried a–d polar residues in HIV-1 gp41 CHR can be mutated as a means of developing new fusion inhibitors against drug-resistant HIV-1 strains. The concept can also be utilized to design fusion inhibitors against other viruses with similar mechanisms.

DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes

ABSTRACT Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.

A Structure-Activity Relationship Study for 2′-Deoxyadenosine Analogs at A9 Position in the Catalytic Core of 10-23 DNAzyme for Rate Enhancement

Modification on the catalytic core of 10-23 DNAzyme with protein-like functional groups is a potential approach to obtain its more efficient analogs. In our efforts for this purpose, a lead structure (DZ-2-9) with 8-aza-7-deaza-2-deoxyadenosine at the A9 position in its catalytic core was obtained. Here we report our structure-activity relationship studies on this lead structure. Various functional groups of different chemical properties were introduced through the 7-substituents of 8-aza-7-deaza-2-deoxyadenosine to DZ-2-9. The functional groups capable of forming hydrogen bonds, like amino and hydroxyl groups, are more favorable for catalytic rate enhancement than the large groups with spacial occupation, like phenyl and tert-butylphenyl groups, and the flexible alkyl linkage was the more preferred choice for optimizing their positive effect. Furthermore, they exerted positive effect cooperatively with the N8 atom. These results give us a clear hint in the design of compounds for A9 substitution of 10-23 DNAzyme for more efficient DNAzymes.

Synthesis of Ring-Contracted Erythromycin A Derivatives via Microwave-Assisted Intramolecular Transesterification

The synthesis of ring-contracted derivatives of erythromycin A via intramolecular transesterification under microwave irradiation of 8,9-anhydroerythromycin A 6,9-hemiketal and its derivatives is described. It was found that microwave irradiation could significantly improve the yields and shorten the reaction times under either solvent-containing (method A) or solvent-free (method B) conditions.

MICROWAVE-ASSISTED SYNTHESIS OF ERYTHROMYCIN DERIVATIVES ON SODIUM ACETATE-DOPED CALCIUM CHLORIDE

Erythromycin (la) has been clinically used for more than 50 years. In addition to its antimicrobial effect, the unique anti-inflammatory activity of erythromycin derivatives has been reported as a new therapeutic p~tential .~ In our effort to maximize the anti-inflammatory activity of erythromycin, the derivative of erythromycin (3a), which exhibited potent in vitro anti-inflammatory a~tivity,~ was selected as one of our target compounds. The conventional synthesis of 3a involves the intramolecular transesterification of 8,9anhydroerythromycin 6,9-hemiketal (2a), obtained by dehydration of l a dissolved in glacial acetic acid, with potassium carbonate in refluxing methanol for 90 r n i ~ ~ . ~ The overall yield of the two steps is 37%. On the other hand, compound 3a could be prepared directly by heating la at 70°C for 24 hr with a 3:1 mixture of pyridine and acetic acid to afford a mixture of 2a and 3a in 19% and 71% yields re~pectively.~ Herein, we report a facile and straightforward synthesis of 3a from la under microwave irradiation in the absence of solvents.