1. TXM peptides inhibit SARS-CoV-2 infection, syncytia formation, and lower inflamatory consequencesTea Govednik, Duško Lainšček, Urška Kuhar, Marva Lachish, Sandra Janežič, Malan Štrbenc, Uroš Krapež, Roman Jerala, Daphne Atlas, Mateja Manček Keber, 2024, original scientific article Abstract: After three years of the SARS-CoV-2 pandemic, the search and availability of relatively low-cost benchtop therapeutics for people not at high risk for a severe disease are still ongoing. Although vaccines and new SARS-CoV-2 variants reduce the death toll, the long COVID-19 along with neurologic symptoms can develop and persist even after a mild initial infection. Reinfections, which further increase the risk of sequelae in multiple organ systems as well as the risk of death, continue to require caution. The spike protein of SARS-CoV-2 is an important target for both vaccines and therapeutics. The presence of disulfide bonds in the receptor binding domain (RBD) of the spike protein is essential for its binding to the human ACE2 receptor and cell entry. Here, we demonstrate that thiol-reducing peptides based on the active site of oxidoreductase thioredoxin 1, called thioredoxin mimetic (TXM) peptides, can prevent syncytia formation, SARS-CoV-2 entry into cells, and infection in a mouse model. We also show that TXM peptides inhibit the redox-sensitive HIV pseudotyped viral cell entry. These results support disulfide targeting as a common therapeutic strategy for treating infections caused by viruses using redox-sensitive fusion. Furthermore, TXM peptides exert anti-inflammatory properties by lowering the activation of NF-κB and IRF signaling pathways, mitogen-activated protein kinases (MAPKs) and lipopolysaccharide (LPS)-induced cytokines in mice. The antioxidant and anti-inflammatory effects of the TXM peptides, which also cross the blood-brain barrier, in combination with prevention of viral infections, may provide a beneficial clinical strategy to lower viral infections and mitigate severe consequences of COVID-19. Keywords: SARS-CoV-2, Disulfides, Thiol-reacting compound, Spike, Anti-inflammatory activity Published in DiRROS: 06.02.2024; Views: 457; Downloads: 187
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2. Postulates for validating TLR4 agonistsMateja Manček Keber, Roman Jerala, 2015, review article Abstract: TLRs play a central role in the innate immune response, recognizing a variety of molecular
structures characteristic of pathogens. Although TLR4, together with its co-receptor
myeloid differentiation-2 (MD-2), recognize bacterial LPS and therefore Gram-negative
bacterial infections, it also plays a key role in many other pathophysiological processes,
including sterile inflammation and viral infection. Specifically, numerous endogenous
agonists of TLR4 of notably diverse nature, ranging from proteins to metal ions, have
been reported. Direct activation of a single receptor by such a range of molecular signals
is very difficult to explain from a structural and mechanistic point of view. It is likely
that only a subset of these directly activate the TLR4–MD-2 complex. We propose three
postulates aimed at distinguishing the direct agonists of TLR4 from indirect activators.
These postulates are as follows: (i) that the agonist requires the TLR4/MD-2 receptor complex;
(ii) that agonist formed synthetically or in situ must activate the receptor complex
in order to eliminate artifacts of contamination by other agonists; and (iii) that a specific
molecular interaction between the agonist and TLR4/MD-2 must be identified. The same
type of postulates can be applied to pattern recognition receptors in general. Keywords: TLR4 agonists, molecular mechanism, ligand recognition Published in DiRROS: 26.01.2015; Views: 5138; Downloads: 519
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