Biology subjects

Ugurlu, H.

Publications and source records attributed to Ugurlu, H..

3 recordsLinked to original sources

bioRxiv2024

Altered spike dynamics drives immune evasion of SARS-CoV-2

Escape from protective immunity has been a defining feature of the COVID-19 pandemic and is widely attributed to mutations in neutralizing antibody epitopes within the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. We investigated whether this paradigm accounts for the escape of Omicron lineage viruses from broadly neutralizing antibodies (bNAbs) targeting conserved RBD epitopes. We found that mutational erosion of bNAb binding epitopes was not a major driver of Omicron immune escape. Viruses carrying RBDs from highly resistant contemporary Omicron variants were potently neutralized by bNAbs when those RBDs were placed into an ancestral Wuhan-like spike backbone. Similarly, sera collected during the pre-Omicron era from individuals vaccinated with Wuhan-based vaccines retained robust RBD-specific neutralizing activity against these chimeric viruses. Mechanistically, bNAb treatment triggered exposure of the S2 cleavage site in neutralization-sensitive but not resistant spike proteins, indicating that bNAb susceptibility reflects differences in spike propensity for antibody-induced premature conformational transition. These findings show that, rather than escaping through mutation of bNAb epitopes, SARS-CoV-2 has evolved spike variants with altered conformational dynamics that resist bNAb-induced destabilization of the prefusion spike trimer.

immunology↗

bioRxiv2021

Intranasal inhibitor blocks Omicron and other variants of SARS-CoV-2

The recent emergence of novel SARS-CoV-2 variants capable of efficiently escaping neutralizing antibodies emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Nasal epithelium is rich in the ACE2 receptor and important for SARS-CoV-2 transmission by supporting early viral replication before seeding to the lung1. Intranasal administration of SARS-CoV-2 neutralizing antibodies or antibody fragments has shown encouraging potential as a protective measure in animal models2-5. However, there remains a dire need for SARS-CoV-2 blocking agents that are less vulnerable to mutational variation in the neutralization epitopes of the viral spike glycoprotein and more economical to produce in large scale. Here we describe TriSb92, a highly manufacturable and extremely stable trimeric human SH3 domain-derived antibody mimetic targeted against a conserved region in the receptor-binding domain of spike. TriSb92 potently neutralizes SARS-CoV-2 and its variants of concern, including Omicron BA.5 as well as the latest and most immunoevasive variants like BF.7, XBB, and BQ.1.1. Intranasal administration of a modest dose of TriSb92 (5 or 50 micrograms) as early as eight hours before a challenge with SARS-CoV-2 efficiently protected mice from infection, and was still effective even when given 4 h after the viral challenge. The target epitope of TriSb92 was defined by cryo-EM, which revealed triggering of a conformational shift in the spike trimer rather than competition for ACE2 binding as the molecular basis of its strong inhibitory action. The high potency and robust biochemical properties of TriSb92 together with the remarkable resistance of its inhibitory action against viral sequence evolution suggest that TriSb92 could be useful as a nasal spray for protecting susceptible individuals from SARS-CoV-2 infection.

microbiology↗

bioRxiv2021

Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro

Background and PurposeRepurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Experimental ApproachSeveral antidepressant drugs and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7 and B.1.351. Key ResultsSeveral clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the (B.1) lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudo viruses with N501Y, K417N, and E484K spike mutations, and the VoC-1 (B.1.1.7) and VoC-2 (B.1.351) variants of SARS-CoV-2. Conclusion and ImplicationsOur study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern.

pharmacology and toxicology↗