The C5a receptor’s (C5aR1) physiological function in various tissues depends on its high-affinity binding to the cationic proinflammatory glycoprotein C5a, produced during the activation of the complement system. However, an overstimulated complement can quickly alter the C5a–C5aR1 function from physiological to pathological, as has been noted in the case of several chronic inflammation-induced diseases like asthma, lung injury, multiorgan failure, sepsis, and now COVID-19. In the absence of the structural data, the current study provides the confirmatory biophysical validation of the hypothesized “two-site” binding interactions of C5a, involving (i) the N-terminus (NT) peptide (“Site1”) and (ii) the extracellular loop 2 (ECL2) peptide of the extracellular surface (ECS) of the C5aR1 (“Site2”), as illustrated earlier in the reported model structural complex of C5a–C5aR1. The biophysical and computational data elaborated in the study provides an improved understanding of the C5a–C5aR1 interaction at an atomistic resolution, highlighting the energetic importance of the aspartic acids on the NT-peptide of C5aR1 toward binding of C5a. The current study can potentially advance the search and optimization of new-generation alternative “antibodies” as well as “neutraligands” targeting the C5a to modulate its interaction with C5aR1.
Amino acids are the essential building blocks of both synthetic and natural peptides, which are crucial for biological functions and also important as biological probes for mapping the complex protein–protein interactions (PPIs) in both prokaryotic and eukaryotic systems. Mapping the PPIs through the chemical biology approach provides pharmacologically relevant peptides, which can have agonistic or antagonistic effects on the targeted biological systems. It is evidenced that ≥ 60 peptide-based drugs have been approved by the US-FDA so far, and the number will improve further in the foreseeable future, as ≥ 140 peptides are currently in clinical trials. However, natural peptides often require fine-tuning of their pharmacological properties by strategically replacing the α L -amino acids of the peptides with non-coded amino acids (NCAA), for which codons are absent in the genetic code for biosynthesis of proteins, prior to their applications as therapeutics. Considering the diverse repertoire of the NCAAs, the conformational space of many NCAAs is yet to be explored systematically in the context of the rational design of therapeutic peptides. The current study deciphers the conformational landscape of a few such Cα-substituted aromatic NCAAs (Ing: 2-indanyl- l -Glycine; Bpa: 4-benzoyl- l -phenylalanine; Aic: 2-aminoindane-2-carboxylic acid) both in the context of tripeptides and model synthetic peptide sequences, using alanine (Ala) and proline (Pro) as the reference. The combined data obtained from the computational and biophysical studies indicate the general success of this approach, which can be exploited further to rationally design optimized peptide sequences of unusual architecture with potent antimicrobial, antiviral, gluco-regulatory, immunomodulatory, and anti-inflammatory activities. Supplementary Information The online version contains supplementary material available at 10.1007/s00726-022-03175-z.
Human C5a (h C5a), one of the pro-inflammatory glycoproteins of the complement system is known to undergo production hyperdrive in response to stress and infection. h C5a 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 h C5a, it is logical to consider the h C5a or its precursors as potential drug targets, and thus, we have been rationally pursuing the idea of neutralizing the harmful effect of excessive h C5a, 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 h C5a 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 h C5a can sequentially accommodate more than one raloxifene molecule with an estimated Ki $ 0.5 mM and Ki $ 3.58 mM 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 h C5a, as an alternative combination therapy for possible management of the 'cytokine storm'-related inflammatory diseases, like COVID19.
Rapid global modernization, urbanization, industrialization, and frequent natural processes release toxic heavy metals into the environment such as mercury (Hg), lead (Pb), cadmium (Cd), arsenic (As) and selenium (Se). In the present scenario, soil and water ecosystems are the main environmental alarms. The remediation of contaminated soils and water ecosystems with appropriate approaches is urgently needed. Physical remediation strategies are conventional, expensive, and nonspecific. Phytoremediation is an eco-friendly and fast-growing approach that are accomplished because of uptake of large quantities of toxic heavy metals from the environment. Since, plants are slow-growing and have low biomass that urgently needs to be bioengineered for high biomass. On the other hand, biotechnology helps to identify and isolate the specific gene coding for heavy metal resistance tolerance in plants. Moreover, molecular cloning and the manifestation of heavy metal accumulator genes and degrading enzyme coding genes displayed enhanced remediation rates, which will make the process for large-scale application to remediate faster contamination soils and water. This review has prominence on biotechnological methods and strategies for remediation of heavy metals and metalloid containment from environments. Furthermore, it focuses on the improvements and implications of phytoremediation as well as their operations and applications to clean up toxic pollutants from environments and to improve phytoremediation efficiency to tolerate different heavy metal pollutants highlights future challenges.
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