In cancer therapy, chemotherapeutic drugs frequently encounter multidrug resistance (MDR) induced by the overexpression of drug transporters such as P-glycoprotein (P-gp). Herein, in order to overcome MDR and improve the effectiveness of chemotherapy, we developed a novel pH-sensitive charge-reversal and NO generation liposomal system by modifying a pH-sensitive polymer (PEG-PLL-DMA) on the surface of cationic liposomes for delivering a NO donor (DETA NONOate) and a chemotherapy drug (paclitaxel, PTX) into MDR cells. The proposed liposomal system (PTX/NO/DMA-L) exhibited a distinctive charge-reversal capacity, which was negatively charged under physiological conditions (pH 7.4) but could reverse to positive charge in a tumor microenvironment (pH 6.5) due to the cleavable amide linkages formed between PEG-PLL and DMA, leading to the improvement of cell uptake. Once arrived in the endosomes and lysosomes (pH 5.0), DETA NONOate was triggered to decompose and release NO, which further promoted the quick release of PTX and inhibited the P-gp mediated efflux. The charge-reversal, NO generation and NO-triggered rapid release of drugs could significantly increase the accumulation of PTX in tumors and eventually improve the antitumor efficacy. These results indicate that this dual pH-sensitive liposomal system is a highly promising approach for chemotherapy and may pave a new avenue for overcoming MDR in cancer.

A dual pH-sensitive liposomal system with charge-reversal and NO generation for overcoming multidrug resistance in cancer.

To date, a number of mannose-binding lectins have been isolated and characterized from plants and fungi. These proteins are composed of different structural scaffold structures which harbor a single or multiple carbohydrate-binding sites involved in the specific recognition of mannose-containing glycans. Generally, the mannose-binding site consists of a small, central, carbohydrate-binding pocket responsible for the "broad sugar-binding specificity" toward a single mannose molecule, surrounded by a more extended binding area responsible for the specific recognition of larger mannose-containing N-glycan chains. Accordingly, the mannose-binding specificity of the so-called mannose-binding lectins towards complex mannose-containing N-glycans depends largely on the topography of their mannose-binding site(s). This structure⁻function relationship introduces a high degree of specificity in the apparently homogeneous group of mannose-binding lectins, with respect to the specific recognition of high-mannose and complex N-glycans. Because of the high specificity towards mannose these lectins are valuable tools for deciphering and characterizing the complex mannose-containing glycans that decorate both normal and transformed cells, e.g., the altered high-mannose N-glycans that often occur at the surface of various cancer cells.

https://hal-amu.archives-ouvertes.fr/hal-02388775/document

Overview of the Structure–Function Relationships of Mannose-Specific Lectins from Plants, Algae and Fungi

Insights into anti-pathogenic activities of mannose lectins.

Pathogenic enveloped viruses are covered with a glycan shield that provides a dual function: the glycan structures contribute to virus protection as well as host cell recognition. The three classical types of N-glycans, in particular complex glycans, high-mannose glycans, and hybrid glycans, together with some O-glycans, participate in the glycan shield of the Ebola virus, influenza virus, human cytomegalovirus, herpes virus, human immunodeficiency virus, Lassa virus, and MERS-CoV, SARS-CoV, and SARS-CoV-2, which are responsible for respiratory syndromes. The glycans are linked to glycoproteins that occur as metastable prefusion glycoproteins on the surface of infectious virions such as gp120 of HIV, hemagglutinin of influenza, or spike proteins of beta-coronaviruses. Plant lectins with different carbohydrate-binding specificities and, especially, mannose-specific lectins from the Vicieae tribe, such as pea lectin and lentil lectin, can be used as glycan probes for targeting the glycan shield because of their specific interaction with the α1,6-fucosylated core Man3GlcNAc2, which predominantly occurs in complex and hybrid glycans. Other plant lectins with Neu5Ac specificity or GalNAc/T/Tn specificity can also serve as potential glycan probes for the often sialylated complex glycans and truncated O-glycans, respectively, which are abundantly distributed in the glycan shield of enveloped viruses. The biomedical and therapeutical potential of plant lectins as antiviral drugs is discussed.

https://www.mdpi.com/2073-4409/11/3/339/pdf?version=1643286259

Legume Lectins with Different Specificities as Potential Glycan Probes for Pathogenic Enveloped Viruses

DdeL, a novel thermostable lectin from Dypsis decaryi seeds: Biological properties

Biochemical characterisation of lectin from Indian hyacinth plant bulbs with potential inhibitory action against human cancer cells

Pathogenic RNA viruses are emerging as one of the major threats and posing challenges to human community. RNA viruses have an exceptionally shorter generation time and easy to adapt in host cells. The recent emergence of SARS-CoV-2, a long RNA virus, has shown us how difficult it is to overcome this kind of pandemic without understanding the viral infection and replication mechanisms. It is essential to comprehend replications of the viral genome, including RNA polymerization and the final capping process. The mRNAs of SARS-CoV-2 coronaviruses are protected at their 5'-ends by cap structure. The cap-like system plays a significant role in viral translational process, viral RNA stability, and scatting in detecting innate immune recognition in host cells. Two coronavirus enzymes, Nsp14 and Nsp16, critically help in the formation of capping and are considered as potential drug targets for antiviral therapy. Natural and herbal medicines have a past record of treating various acute respiratory diseases. In this work, we have exploited 56000 natural compounds to screen potential inhibitors against NSP16. In silico virtual screening, docking and Molecular Dynamics (MD) simulation studies were performed to understand how these potential inhibitors are bound to NSP16. We observed that the most highly screened compound binds to protein molecules with a high dock score, primarily through hydrophobic interactions and hydrogen bonding, as previously reported for NSP16. Compound-13 (2-hydroxy-N-({1-[2-hydroxy-1-(hydroxymethyl)ethyl]piperidin-3-yl}methyl)-5-methylbenzamide) and compound-51 (N-(2-isobutoxybenzyl)-N,2-dimethyl-2,8-diazaspiro[4.5]decane-3-carboxamide) occupied in active site along with good pharmokinetices properties. In conclusion, the selected compounds could be used as a novel therapeutic against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Identification and structural studies of natural inhibitors against SARS-CoV-2 viral RNA methyltransferase (NSP16).

Adenosine deaminase is a zinc+2 dependent key enzyme of purine metabolism which irreversibly converts adenosine to inosine and form ammonia. Overexpression of adenosine deaminase has been linked to a variety of pathophysiological conditions such as atherosclerosis, hypertension, and diabetes. In the case of a cell-mediated immune response, ADA is thought to be a marker, particularly in type II diabetes. Deoxycoformycin is the most potent ADA inhibitor that has been discovered so far, but it has several drawbacks, including being toxic and having poor pharmacokinetics. Taxifolin, a flavonoid derived from plants, was discovered to be a potent inhibitor of the human ADA (hADA) enzyme in the current study. Taxifolin bound at the active site of human ADA and showed fifty percent inhibition at a concentration of 400 µM against the enzyme. To better understand the interactions between taxifolin and human ADA, docking and molecular dynamic simulations were performed. In-silico studies using autodock revealed that taxifolin bound in the active site of human ADA with a binding energy of -7.4 kcal mol -1 and a theoretical Ki of 3.7 uM. Comparative analysis indicated that taxifolin and deoxycoformycin share a common binding space in the active site of human ADA and inhibit its catalytic activity similarly. The work emphasises the need of employing taxifolin as a lead chemical in order to produce a more precise and effective inhibitor of the human ADA enzyme with therapeutic potential.Communicated by Ramaswamy H. Sarma.

Ravindra Singh Rawat

Papers

Biochemical characterisation of lectin from Indian hyacinth plant bulbs with potential inhibitory action against human cancer cells

Identification and structural studies of natural inhibitors against SARS-CoV-2 viral RNA methyltransferase (NSP16).

Understanding the mode of inhibition and molecular interaction of taxifolin with human adenosine deaminase.