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Introduction: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned itself into a pandemic taking a heavy toll on human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive sense single-stranded enveloped virus and quite closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced. Methods: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes nonstructural proteins like RNA dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are in the advanced stage of clinical trials including Remdesivir. While performing close investigation of the large set of nucleic acid based drugs, we were surprised to find that the synthetic nucleic acid backbone is explored very little or rare. Results: We have designed scaffolds derived from peptide nucleic acid (PNA) and subjected them for in-silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess similar binding affinity as Remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 (12,000mg/kg) as opposed to Remdesivir (LD50 =1000mg/kg). Conclusion: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid derived compounds can serve as a leading scaffold to design, synthesize and evaluate many of similar compounds for the treatment of COVID-19.

Peptides are signaling epitopes that control many vital biological events. Increased specificity, synthetic feasibility with concomitant lack of toxicity, and immunogenicity make this emerging class of biomolecules suitable for different applications including therapeutics, diagnostics, and biomedical engineering. Further, chitosan, a naturally occurring linear polymer composed of d-glucosamine and N-acetyl-d-glucosamine units, possesses anti-microbial, muco-adhesive, and hemostatic properties along with excellent biocompatibility. As a result, chitosan finds application in drug/gene delivery, tissue engineering, and bioimaging. Despite these applications, chitosan demonstrates limited cell adhesion and lacks biosignaling. Therefore, peptide-chitosan hybrids have emerged as a new class of biomaterial with improved biosignaling properties and cell adhesion properties. As a result, recent studies encompass increased application of peptide-chitosan hybrids as composites or conjugates in drug delivery, cell therapy, and tissue engineering and as anti-microbial material. This review discusses the recent investigations involving chitosan-peptide materials and uncovers various aspects of these interesting hybrid materials for biomedical applications.

Developed in the early 1990s, peptide nucleic acid (PNA) has emerged as a promising class of nucleic acid mimic because of its strong binding affinity and sequence selectivity toward DNA and RNA and resistance to enzymatic degradation by proteases and nucleases; however, the main drawbacks, as compared to other classes of oligonucleotides, are water solubility and biocompatibility. Herein we show that installation of a relatively small, hydrophilic (R)-diethylene glycol ("miniPEG", R-MP) unit at the γ-backbone transforms a randomly folded PNA into a right-handed helix. Synthesis of optically pure (R-MP)γPNA monomers is described, which can be accomplished in a few simple steps from a commercially available and relatively cheap Boc-l-serine. Once synthesized, (R-MP)γPNA oligomers are preorganized into a right-handed helix, hybridize to DNA and RNA with greater affinity and sequence selectivity, and are more water soluble and less aggregating than the parental PNA oligomers. The results presented herein have important implications for the future design and application of PNA in biology, biotechnology, and medicine, as well as in other disciplines, including drug discovery and molecular engineering.

Addition of bromoform to conjugated nitroalkenes in the presence of Mg provided beta-tribromomethyl nitroalkanes in good to excellent yields and diastereoselectivity. These novel Michael adducts, formed under radical conditions, underwent elimination of HBr in the same pot under reflux to afford beta-dibromomethylenated nitroalkanes in good yield. Alternatively, a one-pot high yielding synthesis of the dibromides was possible under anionic conditions via LDA mediated addition of bromoform to nitroalkenes.

A general method for preparing optically pure guanidine-based gamma-peptide nucleic acid (gammaGPNA) monomers for all four natural nucleobases (A, C, G, and T) is described. These second-generation gammaGPNAs differ from the first-generation GPNAs in that the guanidinium group is installed at the gamma- instead of the alpha-position of the N-(2-aminoethyl)glycine backbone unit. This positional switch enables GPNAs to be synthesized from relatively cheap L- as opposed to D-amino acids. Unlike their alpha-predecessors, which are randomly folded, gammaGPNAs prepared from L-amino acids are preorganized into a right-handed helix and bind to DNA and RNA with exceptionally high affinity and sequence selectivity and are readily taken up by mammalian cells.

Nucleic acids are an attractive platform for organizing molecular self-assembly because of their specific nucleobase interactions and defined length scale. Routinely employed in the organization and assembly of materials in vitro, however, they have rarely been exploited in vivo, due to the concerns for enzymatic degradation and cross-hybridization with the host's genetic materials. Herein we report the development of a tight-binding, orthogonal, synthetically versatile, and informationally interfaced nucleic acid platform for programming molecular interactions, with implications for in vivo molecular assembly and computing. The system consists of three molecular entities: the right-handed and left-handed conformers and a nonhelical domain. The first two are orthogonal to each other in recognition, while the third is capable of binding to both, providing a means for interfacing the two conformers as well as the natural nucleic acid biopolymers (i.e., DNA and RNA). The three molecular entities are prepared from the same monomeric chemical scaffold, with the exception of the stereochemistry or lack thereof at the γ-backbone that determines if the corresponding oligo adopts a right-handed or left-handed helix, or a nonhelical motif. These conformers hybridize to each other with exquisite affinity, sequence selectivity, and level of orthogonality. Recognition modules as short as five nucleotides in length are capable of organizing molecular assembly.

A convenient method for the two-step synthesis of arenediynes from 1,2-arenedialdehydes is reported. Dibromomethylenation of dialdehydes under Corey–Fuchs conditions (CBr4, Ph3P, Zn) provides the tetrabromides in excellent yields. Treatment of the tetrabromides with n-BuLi or LDA affords 3,4-unsaturated 1,5-diynes, the key structural moiety present in several naturally occurring antitumour antibiotics, in varying yields. The key intermediates in these transformations appear to be vinylidenecarbenes or carbenoids, generated in situ via metal–halogen exchange and elimination., © Elsevier

γ-PNA, a new class of peptide nucleic acids, promises to overcome previous sequence limitations of double-stranded DNA (dsDNA) targeting with PNA. To check the potential of γ-PNA, we have synthesized a biotinylated, pentadecameric γ-PNA of mixed sequence carrying three guanidinium G-clamp nucleobases. We have found that strand invasion reactions of the γ-PNA oligomer to its fully complementary target within dsDNA occurs with significantly higher binding rates than to targets containing single mismatches. Association of the PNA oligomer to mismatched targets does not go to completion but instead reaches a stationary level at or below 60%, even at conditions of very low ionic strength. Initial binding rates to both matched and mismatched targets experience a steep decrease with increasing salt concentration. We demonstrate that a linear DNA target fragment with the correct target sequence can be purified from DNA mixtures containing mismatched target or unrelated genomic DNA by affinity capture with streptavidin-coated magnetic beads. Similarly, supercoiled plasmid DNA is obtained with high purity from an initial sample mixture that included a linear DNA fragment with the fully complementary sequence. Based on the results obtained in this study we believe that γ-PNA has a great potential for specific targeting of chosen duplex DNA sites in a sequence-unrestricted fashion.

In this communication, we show that peptide nucleic acids (PNAs) with lengths of 15-20 nucleotides, when preorganized into a right-handed helix, can invade mixed-sequence double-helical B-form DNA (B-DNA). Strand invasion occurs in a highly sequence-specific manner through direct Watson-Crick base pairing. Unlike the previously developed double-duplex invasion strategy, which requires simultaneous binding of two strands of pseudocomplementary PNAs to DNA, only a single strand of gammaPNA is required for invasion in this case, and no nucleobase substitution is needed.

Addition of bromoform to conjugated nitroalkenes in the presence of Mg provided β-tribromomethyl nitroalkanes in good to excellent yields and diastereoselectivity. These novel Michael adducts, formed under radical conditions, underwent elimination of HBr in the same pot under reflux to afford β-dibromomethylenated nitroalkanes in good yield. Alternatively, a one-pot high yielding synthesis of the dibromides was possible under anionic conditions via LDA mediated addition of bromoform to nitroalkenes.

Nature uses Watson–Crick base pairings as a means to store and transmit genetic information because of their high fidelity. These specific A–T (or A–U) and G–C nucleobase interactions, in turn, provide chemists and biologists with a general paradigm for designing molecules to bind to DNA and RNA. With knowledge of the sequence information, one can design oligonucleotides to bind to just about any part of these biopolymeric targets simply by choosing the corresponding nucleobase sequence according to these digital base-pairing rules. Although conceptually simple, such principles in general can only be applied to the recognition of single-stranded DNA or RNA, but not the double-stranded form. The reason is that in double-helical DNA (or RNA) not only are the Watson–Crick faces of the nucleobases already occupied, they are buried within the double helix. [1] Such molecular encapsulation imposes a steep energetic barrier on the designer molecules. To establish binding, not only would they need to be able to gain access to the designated nucleobase targets, which are blocked by the existing base pairs, they would also need to be able to compete with the complementary DNA strand to prevent it from re-annealing with its partner—a task that has rarely been accomplished by any class of molecules. To circumvent this challenge, most of the research effort to date has been focused on establishing principles for recognizing chemical groups in the minor and major groove instead because they are more readily accessible and energetically less demanding. [2] While impressive progress has been made on this front, especially in the development of triplex-forming oligonucleotides, [3–5] polyamides, [6–8] and zinc-finger-binding pep

The synthesis of 3,4-ene-1,5-diynes, the key structural moiety present in several naturally occurring antitumor antibiotics, from 1,2-enedialdehydes under two different experimental conditions is reported. One method involves the dibromomethylenation of dialdehydes under Corey–Fuchs conditions (CBr4, Ph3P, and Zn) and treatment of the resulting tetrabromides with nBuLi or LDA to afford enediynes. The second method involves a base-mediated reaction of enedialdehydes with diethyl (1-diazo-2-oxopropyl)phosphonate (Bestmann–Ohira reagent) and subsequent transformation of the bis(diazo) compounds generated in situ to enediynes. While the transformation of bis(diazo) compounds to enediynes could take place exclusively through alkylidenecarbenes, generated in situ by geminal elimination of N2, an alternative pathway, involving the vicinal elimination of HBr to afford an intermediate bromoalkyne and its subsequent metal-halogen exchange and protonation during workup, exists for the bis(dibromoalkylidenes). However, our deuterium- labeling experiments with a model substrate, deuterated p-methoxybenzylidene dibromide, established the predominance of the alkylidenecarbenes, generated in situ by metal-halogen exchange and elimination, for this substrate and, by analogy, for the tetrabromides as well. The scope of this novel methodology was extended to the synthesis of various heteroatom-based (S, Se, and P) enediynes by quenching the acetylides with suitable electrophiles., © WILEY-VCH Verlag GmbH & Co. KGaA