Biology subjects

Zahedifard, F.

Publications and source records attributed to Zahedifard, F..

3 recordsLinked to original sources

bioRxiv2024

Targeted protein degradation of the CPSF complex by benzoxaboroles through sumoylation

Benzoxaboroles (BoBs) feature a boron-heterocyclic core and are an important innovation in the development of drugs against a range of pathogens and other pathologies. A broad spectrum of pharmacology is associated with chemically diverse BoB derivatives and includes multiple modes-of-action (MoA) and targets. However, a consensus MoA for BoBs targeting evolutionarily diverse protozoan pathogens has emerged with the identification of CPSF3/CPSF73 in the CPSF complex in both apicomplexan and kinetoplastida parasites. Here we establish a functional connection between protein sumoylation and the boron-heterocyclic scaffold shared by all BoBs using comprehensive genetic screens in Trypanosoma brucei. There is a rapid temporal and spatial shift in global protein sumoylation following BoB exposure and members of the CPSF complex are specifically destabilised in a SUMO and proteosome-dependent manner. Finally, we find rapid decrease in bulk mRNA levels, consistent with the role of CPSF3 in mRNA maturation. We propose that a combination of direct inhibition coupled with targeted degradation of CPSF3 underpins the specificity of BoBs against trypanosomatids.

cell biology↗

bioRxiv2023

Beyond the VSG Layer: Exploring the Role of Intrinsic Disorder in the Invariant Surface Glycoproteins of African Trypanosomes

In the bloodstream of mammalian hosts, African trypanosomes face the challenge of protecting their invariant surface receptors from immune detection. This crucial role is fulfilled by a dense, glycosylated protein layer composed of variant surface glycoproteins (VSGs), which undergo antigenic variation and provide a physical barrier that shields the underlying invariant surface glycoproteins (ISGs). The protective shields limited permeability comes at the cost of restricted access to the extracellular host environment, raising questions regarding the specific function of the ISG repertoire. In this study, we employ an integrative structural biology approach to show that intrinsically disordered membrane-proximal regions are a common feature of members of the ISG superfamily, conferring the ability to switch between compact and elongated conformers. While the folded, membrane-distal ectodomain is buried within the VSG layer for compact conformers, their elongated counterparts would enable the extension beyond it. This dynamic behavior enables ISGs to maintain a low immunogenic footprint while still allowing them to engage with the host environment when necessary. Our findings add further evidence to a dynamic molecular organization of trypanosome surface antigens wherein intrinsic disorder underpins the characteristics of a highly flexible ISG proteome to circumvent the constraints imposed by the VSG coat.

biochemistry↗

bioRxiv2022

Repurposing of mitochondria-targeted tamoxifen: Novel anti-cancer drug exhibits potent activity against major protozoan and fungal pathogens.

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process. Therefore, repurposing drugs with already established clinical application offers an attractive, fast-track approach for novel treatment options. In this study, we show that the anti-cancer drug MitoTam, a mitochondria-targeted analog of tamoxifen, efficiently eliminates a wide range of evolutionarily distinct pathogens in vitro, including pathogenic fungi, Plasmodium falciparum, and several species of trypanosomatid parasites, causative agents of debilitating neglected tropical diseases. MitoTam treatment was also effective in vivo and significantly reduced parasitemia of two medically important parasites, Leishmania mexicana and Trypanosoma brucei, in their respective animal infection models. Functional analysis in the bloodstream form of T. brucei showed that MitoTam rapidly altered mitochondrial functions, particularly affecting cellular respiration, lowering ATP levels, and dissipating mitochondrial membrane potential. Our data suggest that the mode of action of MitoTam involves disruption of the inner mitochondrial membrane, leading to rapid organelle depolarization and cell death. Altogether, MitoTam is an excellent candidate drug against several important pathogens, for which there are no efficient therapies and for which drug development is not a priority. Author SummaryMitoTam, a mitochondrially targeted analog of tamoxifen, is a promising anti-cancer candidate drug acting by accumulating in and destabilizing cell mitochondria. In this study, we analyze its effect on a wide range of evolutionarily distinct and medically important pathogens. These include a) pathogenic fungi, Candida albicans, and Cryptococcus neoformans, ubiquitous opportunistic pathogens that cause life-threatening diseases in immunocompromised or immunologically deficient individuals; b) Plasmodium falciparum, the causative agent of human malaria; and c) several species of trypanosomatid parasites such as Trypanosoma cruzi, responsible for deadly Chagas disease in South America, Trypanosoma brucei, the causative agent of sleeping sickness in Africa, and Leishmania, the etiological agent of leishmaniasis, a spectrum of diseases ranging from usually self-healing but potentially disfiguring cutaneous and mucocutaneous leishmaniasis, to visceral leishmaniasis, which is invariably fatal if left untreated. We show that MitoTam efficiently kills these parasites in laboratory conditions and in the case of trypanosomes and leishmaniases suppress or at least slow down the infection in mouse model.

microbiology↗