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Binding of raloxifene to human complement fragment 5a (^hC5a): a perspective on cytokine storm and COVID19.

ABSTRACT: Human C5a (^hC5a), one of the pro-inflammatory glycoproteins of the complement system is known to undergo production hyperdrive in response to stress and infection. ^hC5a has been associated with the pathogenesis of many chronic and acute diseases, due to its proven ability in triggering the 'cytokine storm', by binding to its cognate receptor C5aR, expressed in myriad of tissues. Given the pleiotropic downstream function of ^hC5a, it is logical to consider the ^hC5a or its precursors as potential drug targets, and thus, we have been rationally pursuing the idea of neutralizing the harmful effect of excessive ^hC5a, by implementing the repurposing strategies for FDA-approved drugs. Indeed, the proof of principle biophysical studies published recently is encouraging, which strongly supports the potential of this strategy. Considering BSA-carprofen as a reference model system, the current study further explores the inherent conformational plasticity of ^hC5a and its effect in accommodating more than one drug molecule cooperatively at multiple sites. The data generated by recruiting a battery of experimental and computational biology techniques strongly suggest that ^hC5a can sequentially accommodate more than one raloxifene molecule with an estimated Ki ∼ 0.5 µM and Ki ∼ 3.58 µM on its surface at non-analogous sites. The study hints at exploration of polypharmacology approach, as a new avenue for discovering synergistic drug molecule pairs, or drug molecules with 'broad-range' binding affinity for targeting the different 'hot spots' on ^hC5a, as an alternative combination therapy for possible management of the 'cytokine storm'-related inflammatory diseases, like COVID19. Communicated by Ramaswamy H. Sarma.

SUBMITTER: Mishra R

PROVIDER: S-EPMC7544936 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the decline of cognition and the presence of neuropathological changes including neuronal loss, neurofibrillary pathology and extracellular senile plaques. A neuroinflammatory process is also triggered and complement activation has been hypothesized to have a relevant role in this local inflammatory response. C5a, a proinflammatory anaphylatoxin generated after complement activation, exerts its chemotactic and inflammatory functions through the CD88 receptor while the more recently discovered C5L2 receptor has been postulated to have an anti-inflammatory role. Previously, we reported that a CD88 specific antagonist (PMX205) decreased the pathology and improved cognition in transgenic models of AD suggesting that C5a/C5aR interaction has an important role in the progression of the disease. METHODS:The present study characterizes the expression of the two receptors for C5a in human brain with confirmed post mortem diagnosis of vascular dementia (VD) or AD as well as age matched controls by immunohistochemistry and Western blot analysis using several antibodies against different epitopes of the human receptors. RESULTS:The CD88 and C5L2 antibodies revealed increased expression of both receptors in AD samples as compared to age-matched controls or VD brain tissue by Western blot and immunohistochemistry, using multiple antibodies and distinct cohorts of brain tissue. Immunostaining showed that both the C5L2 and CD88 antibodies similarly labeled abundant neurofibrillary tangles, neuropil threads and dystrophic neurites associated with plaques in the hippocampus and frontal cortex of AD cases. In contrast, little or no neuronal staining, tangles or dystrophic neurites associated with plaques were observed in control or VD brains. CD88 and C5L2 receptors are associated with both early (AT8) and mature (PHF1) neurofibrillary tangles and can be found either independently or colocalized with each other. CONCLUSIONS:The observed association of CD88 and C5L2 with neurofibrillary pathology suggests a common altered pathway of degradation.

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Binding of raloxifene to human complement fragment 5a (^hC5a): a perspective on cytokine storm and COVID19.

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Dataset Information

Binding of raloxifene to human complement fragment 5a (hC5a): a perspective on cytokine storm and COVID19.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Binding of raloxifene to human complement fragment 5a (^hC5a): a perspective on cytokine storm and COVID19.