Most neurodegenerative diseases such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics.

Leishmaniasis caused by obligate intracellular parasites of genus Leishmania is one of the most neglected tropical diseases threatening 350 million people worldwide. Protein kinases have drawn much attention as potential drug targets due to their important role in various cellular processes. In Leishmania sp. mitogen-activated protein kinase 4 is essential for the parasite survival because of its involvement in various regulatory, apoptotic and developmental pathways. The current study reveals the identification of natural inhibitors of L. donovani mitogen-activated protein kinase-4 (LdMPK4). We have performed in silico docking of 110 natural inhibitors of Leishmania parasite that have been reported earlier and identified two compounds Genistein (GEN) and Chrysin (CHY). The homology model of LdMPK4 was developed, followed by binding affinity studies, and pharmacokinetic properties of the inhibitors were calculated by maintaining ATP as a standard molecule. The modelled structure was deposited in the protein model database with PMDB ID: PM0080988. Molecular dynamic simulation of the enzyme-inhibitor complex along with the free energy calculations over 50 ns showed that GEN and CHY are more stable in their binding. These two molecules, GEN and CHY, can be considered as lead molecules for targeting LdMPK4 enzyme and could emerge as potential LdMPK4 inhibitors.

Protozoan parasites of the Leishmania genus have evolved unique signaling pathways that can sense various environmental changes and trigger stage differentiation for survival and host infectivity. MAP kinase (MAPK) plays a critical role in various cellular activities like cell differentiation, proliferation, stress regulation, and apoptosis. The Leishmania donovani MAPK3 (LdMAPK3) is involved in the regulation of flagella length and hence plays an important role in disease transmission. Here, we reported the gene cloning, protein expression, biochemical characterizations, inhibition studies and cell proliferation assay of LdMAPK3. The recombinant purified LdMAPK3 enzyme obeys the Michaelis-Menten equation with K_m and V_max of LdMAPK3 was found to be 20.23 nM and 38.77 ± 0.71 nmoles ATP consumed/mg LdMAPK3/min respectively. The maximum kinase activity of LdMAPK3 was recorded at 35 °C and pH 7. The in-vitro inhibition studies with two natural inhibitors genistein (GEN) and chrysin (CHY) was evaluated against LdMAPK3. The K_i value for GEN and CHY were found to be 3.76 ± 0.28 µM and K_i = 8.75 ± 0.11 µM respectively. The IC₅₀ value for the compounds, GEN and CHY against L. donovani promastigotes were calculated as 9.9 µg/mL and 13 µg/mL respectively. Our study, therefore, reports LdMAPK3 as a new target for therapeutic approach against leishmaniasis.