Structure-activity relationship in NOD2 agonistic muramyl dipeptides.

Nucleotide-binding oligomerization domain 2 (NOD2) is a receptor of the innate immune system that is capable of perceiving bacterial and viral infections. Muramyl dipeptide (MDP, N-acetyl muramyl L-alanyl-d-isoglutamine), identified as the minimal immunologically active component of bacterial cell wall peptidoglycan (PGN) is recognized by NOD2. In terms of biological activities, MDP demonstrated vaccine adjuvant activity and stimulated non-specific protection against bacterial, viral, and parasitic infections and cancer. However, MDP has certain drawbacks including pyrogenicity, rapid elimination, and lack of oral bioavailability. Several detailed structure-activity relationship (SAR) studies around MDP scaffolds are being carried out to identify better NOD2 ligands. The present review elaborates a comprehensive SAR summarizing structural aspects of MDP derivatives in relation to NOD2 agonistic activity.

Fangchinoline inhibits SARS-CoV-2 and MERS-CoV entry.

The COVID-19 pandemic caused by SARS-CoV-2, lead to mild to severe respiratory illness and resulted in 6.9 million deaths worldwide. Although vaccines are effective in preventing COVID-19, they may not be sufficient to protect immunocompromised individuals from this respiratory illness. Moreover, novel emerging variants of SARS-CoV-2 pose a risk of new COVID-19 waves. Therefore, identification of effective antivirals is critical in controlling SARS and other coronaviruses, such as MERS-CoV. We show that Fangchinoline (Fcn), a bisbenzylisoquinoline alkaloid, inhibits replication of SARS-CoV, SARS-CoV-2, and MERS-CoV in a range of in vitro assays, by blocking entry. Therapeutic use of Fcn inhibited viral loads in the lungs, and suppressed associated airway inflammation in hACE2. Tg mice and Syrian hamster infected with SARS-CoV-2. Combination of Fcn with remdesivir (RDV) or an anti-leprosy drug, Clofazimine, exhibited synergistic antiviral activity. Compared to Fcn, its synthetic derivative, MK-04-003, more effectively inhibited SARS-CoV-2 and its variants B.1.617.2 and BA.5 in mice. Taken together these data demonstrate that Fcn is a pan beta coronavirus inhibitor, which possibly can be used to combat novel emerging coronavirus diseases.

Structure activity relationship in ß-carboline derived anti-malarial agents.

Malaria, even though an avoidable and treatable disease, can be fatal if ignored. Artemisinin Combination Therapy (ACT) and RTS, S/AS01 vaccine (Mosquirix™) are the only modest means available with humans to overcome malaria, a lethal affliction wreaking havoc across the globe. Employment of ACT is associated with problems such as 'Artemisinin Resistance' and the 'Hypnozoite conundrum' that hinder the complete eradication of malaria. In this view, the natural products specifically comprising ß-carboline scaffold have shown good antiplasmodial responses against different strains of malaria. Taking these observations forward, researchers have performed structure-activity relationship (SAR) studies around three different ß-carboline skeletons (tetrahydro ß-carbolines, dihydro ß-carbolines, ß-carbolines) to design new ß-carboline derived heterocyclic structures or modified naturally occurring derivatives. In addition, different approaches such as dimerization and linkage to other moieties have also been adopted to enhance the antimalarial activity. The present review describes a comprehensive SAR study encapsulating various natural and synthetic ß-carbolines to elaborate upon the utility of these skeletons in designing drugs to subdue this deadly disease.