Molecular and therapeutic insights of rapamycin: a multi-faceted drug from Streptomyces hygroscopicus

Abstract

The advancement in pharmaceutical research has led to the discovery and development of new combinatorial life-saving drugs. Rapamycin is a macrolide compound produced from Streptomyces hygroscopicus. Rapamycin and its derivatives are one of the promising sources of drug with broad spectrum applications in the medical field. In recent times, rapamycin has gained significant attention as of its activity against cytokine storm in COVID-19 patients. Rapamycin and its derivatives have more potency when compared to other prevailing drugs. Initially, it has been used exclusively as an anti-fungal drug. Currently rapamycin has been widely used as an immunosuppressant. Rapamycin is a multifaceted drug; it has anti-cancer, anti-viral and anti-aging potentials. Rapamycin has its specific action on mTOR signaling pathway. mTOR has been identified as a key regulator of different pathways. There will be an increased demand for rapamycin, because it has lesser adverse effects when compared to steroids. Currently researchers are focused on the production of effective rapamycin derivatives to combat the growing demand of this wonder drug. The main focus of the current review is to explore the origin, development, molecular mechanistic action, and the current therapeutic aspects of rapamycin. Also, this review article revealed the potential of rapamycin and the progress of rapamycin research. This helps in understanding the exact potency of the drug and could facilitate further studies that could fill in the existing knowledge gaps. The study also gathers significant data pertaining to the gene clusters and biosynthetic pathways involved in the synthesis and production of this multi-faceted drug. In addition, an insight into the mechanism of action of the drug and important derivatives of rapamycin has been expounded. The fillings of the current review, aids in understanding the underlying molecular mechanism, strain improvement, optimization and production of rapamycin derivatives.

Keywords: Autophagy; FKBP-12; Immunosuppressant; Macrolactone; Rapamycin; Streptomyces hygroscopicus; mTOR.

Fig. 1

4,5-dihydroxycyclohex-1-enecarboxylic acid biosynthesis through shikimate pathway. rapK gene code for chorismatase convert chorismite to DCHC. (EPSP: 5-enolpyruvylshikimate-3-phosphate, DCHC: (4R,5R)-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid), DCHC: 4,5-dihydroxycyclohex-1-enecarboxylic acid)

Fig. 2

Biosynthesis of rapamycin. This picture illustrates the biosynthesis of rapamycin linear polyketide chain and the convention of linear chain to circular pre rapamycin. Post tailoring genes convert prerapamycin to rapamycin

Fig. 3

Mechanism of action of rapamycin. This picture illustrates the interaction of rapamycin-FKBP12 complex with FRB domain in the mTOR. This interaction dephosphorylates 4E-BP1, cdks-p27 and P70s kinase and clock cell proliferation, cell cycle arrest and inhibit ribosomal recruitment

Fig. 4

Mechanism of action of rapamycin against progeria. Accumulation of progerin eventually results in the cell cycle arrest. Rapamycin interaction enhanced the autophagy and cleared the accumulation of progerin