The coronavirus membrane protein (M) is the main organizer of coronavirus assembly^1,2,3. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.

Epithelia in the skin, gut and other environmentally exposed organs display a variety of mechanisms to control microbial communities and limit potential pathogenic microbial invasion. Naturally occurring antimicrobial proteins/peptides and their synthetic derivatives (here collectively referred to as AMPs) reinforce the antimicrobial barrier function of epithelial cells. Understanding how these AMPs are functionally regulated may be important for new therapeutic approaches to combat microbial infections. Some AMPs are subject to redox-dependent regulation. This review aims to: (i) explore cysteine-based redox active AMPs in skin and intestine; (ii) discuss casual links between various redox environments of these barrier tissues and the ability of AMPs to control cutaneous and intestinal microbes; (iii) highlight how bacteria, through intrinsic mechanisms, can influence the bactericidal potential of redox-sensitive AMPs.

Tkanki nabłonkowe mają ciągły kontakt ze środowiskiem zewnętrznym, w tym z mikroorganizmami chorobotwórczymi. Wytwarzane przez komórki nabłonkowe endogenne białka i peptydy przeciwdrobnoustrojowe w sposób bezpośredni lub poprzez zaangażowanie do tego celu komórek odpornościowych kontrolują liczebność oraz skład populacji drobnoustrojów. Do tej grupy cząsteczek zaliczane są aktywne pochodne chemeryny, wielofunkcyjnego białka, wyposażonego zarówno w funkcję przeciwdrobnoustrojową, jak i chemotaktyczną. Ze względu na rosnącą liczbę infekcji wywoływanych przez mikroorganizmy niewrażliwe na antybiotyki, takie jak metycylinooporne szczepy gronkowca złocistego (MRSA), niezwykle ważne staje się zrozumienie mechanizmów kontroli drobnoustrojów zasiedlających miejsca barierowe, takie jak skóra i jama ustna. Syntetyczny peptyd 4 (p4), obejmujący centralną sekwencję Val66-Pro85 chemeryny, wykazuje szerokie spektrum aktywności przeciwdrobnoustrojowej przeciwko bakteriom skóry i jamy ustnej, łącznie z lekoopornymi szczepami MRSA. Cechy te czynią z niego peptyd o obiecującym potencjale terapeutycznym. W artykule prezentujemy przegląd ochronnych funkcji chemeryny oraz jej pochodnych w tkance nabłonkowej.

The continued emergence and zoonotic threat posed by coronaviruses highlight the urgent need for effective antiviral strategies with broad reactivity to counter new emerging strains. Nanobodies (or single-domain antibodies) are promising alternatives to traditional monoclonal antibodies, due to their small size, cost-effectiveness and ease of bioengineering. Here, we describe 7F, a llama-derived nanobody, targeting the spike receptor binding domain of sarbecoviruses and SARS-like coronaviruses. 7F demonstrates potent neutralization against SARS-CoV-2 and cross-neutralizing activity against SARS-CoV and SARS-like CoV WIV16 pseudoviruses. Structural analysis reveals 7F’s ability to induce the formation of spike trimer dimers by engaging with two SARS-CoV-2 spike RBDs, targeting the highly conserved class IV region. Bivalent 7F constructs substantially enhance neutralization potency and breadth, up to more recent SARS-CoV-2 variants of concern. Furthermore, we demonstrate the therapeutic potential of 7F against SARS-CoV-2 in the fully differentiated 3D tissue cultures mirroring the epithelium of the human airway ex vivo. The broad sarbecovirus activity and distinctive structural features of 7F underscore its potential as promising antiviral against emerging and evolving sarbecoviruses.